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1
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Wu P, Wen Z. ATM is associated with the prognosis of colorectal cancer: a systematic review. Front Oncol 2025; 15:1470939. [PMID: 40144209 PMCID: PMC11936800 DOI: 10.3389/fonc.2025.1470939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 02/12/2025] [Indexed: 03/28/2025] Open
Abstract
Objective Chemosensitivity and radiosensitivity are associated with the prognosis of colorectal cancer, and the expression of the ataxia-telangiectasia mutated (ATM) protein plays an essential role in these processes. The present study examined the relationship between ATM expression and the survival outcomes of colorectal cancer patients and explored the underlying mechanism and promising therapeutic strategies. Method A search including medical subject headings (MeSH), free terms, and combined words was conducted using Pubmed, EMBASE, and Cochrane. Studies had to meet the inclusion criteria as well as include processes such as data extraction and quality evaluation. The survival outcomes were assessed using hazard ratio (HR) and 95% confidence interval (CI). Heterogeneity, and publication bias were analyzed, and a P value <0.05 was considered statistically significant. Results Nine studies with 2883 patients were included in the meta-analysis. Low ATM expression level was related to poor overall survival (HR=0.542, 95% CI=0.447-0.637; P=0.000). Disease-free, progression-free, and recurrence-free survival rates were lower in patients with low ATM expression than in those with high ATM expression. There was no significant difference between Stage I-II and Stage III-IV colorectal cancer patients [risk ratio (RR)=1.173, 95% CI=0.970-1.417, P=0.690]. Conclusions Low ATM expression level may be a marker of poor survival in colorectal cancer and contributes to resistance to therapy. Targeting related factors in these pathways to sensitize tumors to treatment is a potential therapeutic strategy, and monitoring ATM status could be a valuable guide independent of the immunotherapy or chemotherapy strategy used.
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Affiliation(s)
- Pei Wu
- Department of Gastrointestinal Surgery, Yongchuan Hospital of Chongqing Medical University, Chongqing, China
| | - Zelin Wen
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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2
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Gila F, Khoddam S, Jamali Z, Ghasemian M, Shakeri S, Dehghan Z, Fallahi J. Personalized medicine in colorectal cancer: a comprehensive study of precision diagnosis and treatment. Per Med 2025; 22:59-81. [PMID: 39924822 DOI: 10.1080/17410541.2025.2459050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 01/23/2025] [Indexed: 02/11/2025]
Abstract
Colorectal cancer is a common and fatal disease that affects many people globally. CRC is classified as the third most prevalent cancer among males and the second most frequent cancer among females worldwide. The purpose of this article is to examine how personalized medicine might be used to treat colorectal cancer. The classification of colorectal cancer based on molecular profiling, including the detection of significant gene mutations, genomic instability, and gene dysregulation, is the main topic of this discussion. Advanced technologies and biomarkers are among the detection methods that are explored, demonstrating their potential for early diagnosis and precise prognosis. In addition, the essay explores the world of treatment possibilities by providing light on FDA-approved personalized medicine solutions that provide individualized and precise interventions based on patient characteristics. This article assesses targeted treatments like cetuximab and nivolumab, looks at the therapeutic usefulness of biomarkers like microsatellite instability (MSI) and circulating tumor DNA (ctDNA), and investigates new approaches to combat resistance. Through this, our review provides a thorough overview of personalized medicine in the context of colorectal cancer, ultimately highlighting its potential to revolutionize the field and improve patient care.
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Affiliation(s)
- Fatemeh Gila
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Somayeh Khoddam
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Jamali
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohmmad Ghasemian
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shayan Shakeri
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zeinab Dehghan
- Department of Comparative Biomedical Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jafar Fallahi
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
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de Moraes FCA, de Laia EA, Sano VKT, Dos Santos AGE, Pereira CRM, Burbano RMR. A systematic review and meta-analysis of users versus non-users: unveiling the influence of proton pump inhibitors on capecitabine efficacy in colorectal cancer. Expert Rev Clin Pharmacol 2025; 18:67-75. [PMID: 39690972 DOI: 10.1080/17512433.2024.2443183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 12/07/2024] [Accepted: 12/12/2024] [Indexed: 12/19/2024]
Abstract
INTRODUCTION Colorectal cancer is the second leading cause of cancer-related deaths worldwide. The impact of proton pump inhibitors (PPIs) on patients taking capecitabine, an oral fluoropyrimidine, remains uncertain, despite their use by 20 to 55% of cancer patients. We investigated how PPIs affect the effectiveness of capecitabine in treating colorectal cancer. METHODS We searched PubMed, Embase, and Web of Science databases for studies that investigated the use of PPI with capecitabine versus capecitabine alone. We used random-effects models for all endpoints. Heterogeneity was assessed using I2 statistics. RESULTS We included 676 patients receiving capecitabine monotherapy. The overall progression/disease-free survival favored the PPI non-users (HR 2.1372; 95% CI 1.4591-3.1306; p < 0.001). Our results show that there seems to be no difference between users of PPIs and capecitabine in the colorectal cancer patients (HR 1.5922; 95% CI 0.9718-2.6086; p = 0.065). However, after sensitivity-adjusted analysis, PPI use was negatively associated with PPI use (HR 2.14; 95% CI 1.14-4.01; p < 0.001). CONCLUSION Patients with colorectal cancer undergoing oral chemotherapy, specifically capecitabine, should be monitored for the use of PPIs. Therefore, the use of PPIs should be discouraged in clinical practice in these cases. PROTOCOL REGISTRATION www.crd.york.ac.uk/prospero identifier is CRD42024498240.
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Affiliation(s)
| | | | | | | | - Caroline R M Pereira
- Department of Medicine, State University of Rio de Janeiro (UERJ), Rio de Janeiro, Brazil
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4
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Shahzaib M, Muaz M, Zubair MH, Kayani MUR. MiCK: a database of gut microbial genes linked with chemoresistance in cancer patients. Database (Oxford) 2024; 2024:baae124. [PMID: 39707929 PMCID: PMC11662283 DOI: 10.1093/database/baae124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 11/22/2024] [Accepted: 11/28/2024] [Indexed: 12/23/2024]
Abstract
Cancer remains a global health challenge, with significant morbidity and mortality rates. In 2020, cancer caused nearly 10 million deaths, making it the second leading cause of death worldwide. The emergence of chemoresistance has become a major hurdle in successfully treating cancer patients. Recently, human gut microbes have been recognized for their role in modulating drug efficacy through their metabolites, ultimately leading to chemoresistance. The currently available databases are limited to knowledge regarding the interactions between gut microbiome and drugs. However, a database containing the human gut microbial gene sequences, and their effect on the efficacy of chemotherapy for cancer patients has not yet been developed. To address this challenge, we present the Microbial Chemoresistance Knowledgebase (MiCK), a comprehensive database that catalogs microbial gene sequences associated with chemoresistance. MiCK contains 1.6 million sequences of 29 gene types linked to chemoresistance and drug metabolism, curated manually from recent literature and sequence databases. The database can support downstream analysis as it provides a user-friendly web interface for sequence search and download functionalities. MiCK aims to facilitate the understanding and mitigation of chemoresistance in cancers by serving as a valuable resource for researchers. Database URL: https://microbialchemreskb.com/.
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Affiliation(s)
- Muhammad Shahzaib
- Metagenomics Discovery Lab, School of Interdisciplinary Engineering and Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan
| | - Muhammad Muaz
- School of Electrical Engineering and Computer Science (SEECS), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan
| | - Muhammad Hasnain Zubair
- Metagenomics Discovery Lab, School of Interdisciplinary Engineering and Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan
| | - Masood Ur Rehman Kayani
- Metagenomics Discovery Lab, School of Interdisciplinary Engineering and Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan
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5
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Zhou Y, Lin S, Zhong X, Huang F, Huang J, Xu L. Oleanolic acid combined with aspirin plays antitumor roles in colorectal cancer via the Akt/NFκB/IκBα/COX2 pathway. Cell Death Discov 2024; 10:504. [PMID: 39695129 DOI: 10.1038/s41420-024-02223-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 07/16/2024] [Accepted: 10/21/2024] [Indexed: 12/20/2024] Open
Abstract
Among the common malignancies, colorectal cancer (CRC) is often resistant to chemotherapy because of drug resistance and severe toxicity. Currently, aspirin is one of the most promising CRC chemopreventive drugs, both for primary prevention and for reducing the chance of recurrence and metastasis following radical surgery in patients with early-stage CRC. Oleanolic acid is a potential antineoplastic drug that has an antagonistic effect on many kinds of tumors. Network pharmacology, molecular docking, and in vitro experiments were performed to investigate whether OA combined with aspirin can enhance the anticancer effects of aspirin. As indicated by the network pharmacology results, oleanolic acid and aspirin can regulate multiple signaling pathways through multiple target proteins, including NFκB1\IκBα\PTGS2\MAPK3\PIK3CA. A series of cellular experiments demonstrated for the first time that oleanolic acid synergistically enhances aspirin to inhibit the proliferation and invasion of HCT116 and HT29 cells and induce S-phase arrest by regulating Akt/NFκB/IκBα/COX2 signaling pathway, thus synergistically enhancing the ability of aspirin to promote apoptosis of colorectal cancer cells. This study provides a novel approach to the use of fresh medications for the treatment of colorectal cancer and offers a theoretical foundation for the potential creation of aspirin derivatives based on oleanolic acid.
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Affiliation(s)
- Yulv Zhou
- Department of Chinese Medicine and Anorectology, Sanming First Hospital, Affiliated Hospital of Fujian Medical University, Sanming City, Fujian Province, China
| | - Shengnan Lin
- Department of Clinical Pharmacy, Sanming First Hospital, Affiliated Hospital of Fujian Medical University, Sanming City, Fujian Province, China
| | - Xinzhu Zhong
- Department of Clinical Pharmacy, Sanming First Hospital, Affiliated Hospital of Fujian Medical University, Sanming City, Fujian Province, China
| | - Fang Huang
- Department of Clinical Pharmacy, Sanming First Hospital, Affiliated Hospital of Fujian Medical University, Sanming City, Fujian Province, China
| | - Jinxiang Huang
- Department of Neurosurgery, The First Affiliated Hospital of Naval Medical University (Changhai Hospital), Naval Medical University, Shanghai, China.
| | - Luning Xu
- Department of Clinical Pharmacy, Sanming First Hospital, Affiliated Hospital of Fujian Medical University, Sanming City, Fujian Province, China.
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Zuraik AA, Daboul Y, Awama MA, Yazigi H, Kayasseh MA, Georges M. Effect of Chemotherapy on Fusobacterium nucleatum Abundance in Colorectal Cancer Patients: A Study on Relapsing Patients. Indian J Microbiol 2024; 64:1938-1950. [PMID: 39678992 PMCID: PMC11645352 DOI: 10.1007/s12088-024-01279-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 04/04/2024] [Indexed: 12/17/2024] Open
Abstract
An intricate relationship exists, and interactions occur between the gut microbiota and colorectal cancer (CRC). Recent studies have indicated that inflammatory reactions stimulated by Fusobacterium nucleatum (Fn) lead to the development of CRC. Radical surgery combined with adjuvant chemotherapy is the primary treatment approach for most CRC patients. This study was designed to evaluate the abundance of Fn as part of the gut microbiota in patients with CRC compared to healthy individuals and to assess the effect of the gut microbiota Fn on patients undergoing adjuvant chemotherapy and those experiencing CRC relapse. There were 201 participants, comprising 50 healthy controls and 151 CRC patients. Stool samples were collected from three CRC groups (postoperatively, chemotherapy and relapse), and the fourth was the healthy control group. The amount of Fn in each sample was analyzed using quantitative loop-mediated isothermal amplification-phenol red (QLAMP-PhR), a novel biomolecular method that targets regions encoding the specific Fn FadA gene. Compared with healthy control stool samples, the Fn levels were significantly elevated in all CRC patient groups (P < 0.001), and it was significantly more frequent in the CRC relapse patients (group C) (P < 0.001). In addition, Fn abundance increased significantly in the distal colon compared to the proximal colon (P < 0.001). Both CRC relapse and chemotherapy exert significant reciprocal effects on the gut microbiota Fn of CRC patients. Microbiota-based intervention may be beneficial for patients during postoperative care, especially in CRC relapsing cases. Registration: This study of the clinical trial has been registered in the ISRCTN registry with study registration number ISRCTN53358464. https://www.isrctn.com/ISRCTN53358464. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s12088-024-01279-6.
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Affiliation(s)
- Abdulrahman A. Zuraik
- Department of Biochemistry and Microbiology, Faculty of Pharmacy, Tishreen University, Lattakia, Syria
| | - Yaman Daboul
- School of Biological Sciences, Queens University Belfast, Belfast, UK
| | - M. Ayman Awama
- Department of Biochemistry and Microbiology, Faculty of Pharmacy, Tishreen University, Lattakia, Syria
| | - Haitham Yazigi
- Department of Laboratory Medicine/Faculty of Medicine, Tishreen University & Tishreen University Hospital, Lattakia, Syria
| | - Moh’d Azzam Kayasseh
- Dr. Kayasseh Medical Clinic, Dr. Sulaiman Al Habib Medical Group, DHCC, Dubai, UAE
| | - Michael Georges
- Department of Oncology, Faculty of Medicine, Tishreen University & Tishreen University Hospital, Lattakia, Syria
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Kim J, Jeong Y, Shin YM, Kim SE, Shin SJ. FL118 Enhances Therapeutic Efficacy in Colorectal Cancer by Inhibiting the Homologous Recombination Repair Pathway through Survivin-RAD51 Downregulation. Cancers (Basel) 2024; 16:3385. [PMID: 39410005 PMCID: PMC11475853 DOI: 10.3390/cancers16193385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/30/2024] [Accepted: 10/01/2024] [Indexed: 10/20/2024] Open
Abstract
Background/Objectives: Irinotecan, a camptothecin (CPT) derivative, is commonly used as a first-line therapy for colorectal cancer (CRC), but resistance remains a significant challenge. This study aims to explore the therapeutic potential of FL118, another CPT derivative, with a focus on overcoming resistance to irinotecan. Methods: The effects of FL118 on CRC cells were evaluated, and bioinformatics analysis was performed on RNA-seq data. Transfection was conducted to observe the knockdown effect of survivin, and the in vivo efficacy of FL118 was assessed using a xenograft model. Results: FL118 induces apoptosis, G2/M arrest, and DNA damage. A notable mechanism of action of FL118 is a reduction in survivin levels, which downregulates the expression of RAD51, a key marker of homologous recombination, and attenuates DNA repair processes. Given that SN38 is the active metabolite of irinotecan, FL118 reduces cell viability and RAD51 in SN38-resistant LOVO cells. Conclusions: Our findings provide effective insights into the antitumor activity of FL118 and its potential as a therapeutic agent for overcoming irinotecan resistance in CRC.
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Affiliation(s)
- Jungyoun Kim
- Department of Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (J.K.); (Y.J.); (Y.M.S.); (S.E.K.)
- Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Yeyeong Jeong
- Department of Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (J.K.); (Y.J.); (Y.M.S.); (S.E.K.)
- Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - You Me Shin
- Department of Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (J.K.); (Y.J.); (Y.M.S.); (S.E.K.)
- Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Sung Eun Kim
- Department of Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (J.K.); (Y.J.); (Y.M.S.); (S.E.K.)
- Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Sang Joon Shin
- Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
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8
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González A, Badiola I, Fullaondo A, Rodríguez J, Odriozola A. Personalised medicine based on host genetics and microbiota applied to colorectal cancer. ADVANCES IN GENETICS 2024; 112:411-485. [PMID: 39396842 DOI: 10.1016/bs.adgen.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Colorectal cancer (CRC) ranks second in incidence and third in cancer mortality worldwide. This situation, together with the understanding of the heterogeneity of the disease, has highlighted the need to develop a more individualised approach to its prevention, diagnosis and treatment through personalised medicine. This approach aims to stratify patients according to risk, predict disease progression and determine the most appropriate treatment. It is essential to identify patients who may respond adequately to treatment and those who may be resistant to treatment to avoid unnecessary therapies and minimise adverse side effects. Current research is focused on identifying biomarkers such as specific mutated genes, the type of mutations and molecular profiles critical for the individualisation of CRC diagnosis, prognosis and treatment guidance. In addition, the study of the intestinal microbiota as biomarkers is being incorporated due to the growing scientific evidence supporting its influence on this disease. This article comprehensively addresses the use of current and emerging diagnostic, prognostic and predictive biomarkers in precision medicine against CRC. The effects of host genetics and gut microbiota composition on new approaches to treating this disease are discussed. How the gut microbiota could mitigate the side effects of treatment is reviewed. In addition, strategies to modulate the gut microbiota, such as dietary interventions, antibiotics, and transplantation of faecal microbiota and phages, are discussed to improve CRC prevention and treatment. These findings provide a solid foundation for future research and improving the care of CRC patients.
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Affiliation(s)
- Adriana González
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | - Iker Badiola
- Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Asier Fullaondo
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | | | - Adrian Odriozola
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain.
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9
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Hsieh CC, Li TW, Li CC, Chen SH, Wei YL, Chiang NJ, Shen CH. DKK1 as a chemoresistant protein modulates oxaliplatin responses in colorectal cancer. Oncogenesis 2024; 13:34. [PMID: 39333078 PMCID: PMC11436992 DOI: 10.1038/s41389-024-00537-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 09/15/2024] [Accepted: 09/19/2024] [Indexed: 09/29/2024] Open
Abstract
Oxaliplatin is effective against colorectal cancer (CRC), but resistance hampers treatment. We found upregulated Dickkopf-1 (DKK1, a secreted protein) in oxaliplatin-resistant (OR) CRC cell lines and DKK1 levels increased by more than 2-fold in approximately 50% of oxaliplatin-resistant CRC tumors. DKK1 activates AKT via cytoskeleton-associated protein 4 (CKAP4, a DKK1 receptor), modulating oxaliplatin responses in vitro and in vivo. The leucine zipper (LZ) domain of CKAP4 and cysteine-rich domain 1 (CRD1) of secreted DKK1 are crucial for their interaction and AKT signaling. By utilizing the LZ protein, we disrupted DKK1 signaling, enhancing oxaliplatin sensitivity in OR CRC cells and xenograft tumors. This suggests that DKK1 as a chemoresistant factor in CRC via AKT activation. Targeting DKK1 with the LZ protein offers a promising therapeutic strategy for oxaliplatin-resistant CRC with high DKK1 levels. This study sheds light on oxaliplatin resistance mechanisms and proposes an innovative intervention for managing this challenge.
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Affiliation(s)
- Chi-Che Hsieh
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Ting-Wei Li
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan
- Department of Life Sciences, National Cheng Kung University, Tainan, 704, Taiwan
| | - Chun-Chun Li
- Department of Life Sciences, National Cheng Kung University, Tainan, 704, Taiwan
| | - Shang-Hung Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan
| | - You-Lin Wei
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan
| | - Nai-Jung Chiang
- Department of Oncology, Taipei Veterans General Hospital, Taipei, 112, Taiwan.
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
| | - Che-Hung Shen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan.
- Doctoral Program in Tissue Engineering and Regenerative Medicine, Biotechnology Center, National Chung Hsing University, Taichung, 402, Taiwan.
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
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10
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Zhang C, Zheng J, Liu J, Li Y, Xing G, Zhang S, Chen H, Wang J, Shao Z, Li Y, Jiang Z, Pan Y, Liu X, Xu P, Wu W. Pan-cancer analyses reveal the molecular and clinical characteristics of TET family members and suggests that TET3 maybe a potential therapeutic target. Front Pharmacol 2024; 15:1418456. [PMID: 39104395 PMCID: PMC11298443 DOI: 10.3389/fphar.2024.1418456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 05/28/2024] [Indexed: 08/07/2024] Open
Abstract
The Ten-Eleven Translocation (TET) family genes are implicated in a wide array of biological functions across various human cancers. Nonetheless, there is a scarcity of studies that comprehensively analyze the correlation between TET family members and the molecular phenotypes and clinical characteristics of different cancers. Leveraging updated public databases and employing several bioinformatics analysis methods, we assessed the expression levels, somatic variations, methylation levels, and prognostic values of TET family genes. Additionally, we explored the association between the expression of TET family genes and pathway activity, tumor microenvironment (TME), stemness score, immune subtype, clinical staging, and drug sensitivity in pan-cancer. Molecular biology and cytology experiments were conducted to validate the potential role of TET3 in tumor progression. Each TET family gene displayed distinct expression patterns across at least ten detected tumors. The frequency of Single Nucleotide Variant (SNV) in TET genes was found to be 91.24%, primarily comprising missense mutation types, with the main types of copy number variant (CNV) being heterozygous amplifications and deletions. TET1 gene exhibited high methylation levels, whereas TET2 and TET3 genes displayed hypomethylation in most cancers, which correlated closely with patient prognosis. Pathway activity analysis revealed the involvement of TET family genes in multiple signaling pathways, including cell cycle, apoptosis, DNA damage response, hormone AR, PI3K/AKT, and RTK. Furthermore, the expression levels of TET family genes were shown to impact the clinical staging of tumor patients, modulate the sensitivity of chemotherapy drugs, and thereby influence patient prognosis by participating in the regulation of the tumor microenvironment, cellular stemness potential, and immune subtype. Notably, TET3 was identified to promote cancer progression across various tumors, and its silencing was found to inhibit tumor malignancy and enhance chemotherapy sensitivity. These findings shed light on the role of TET family genes in cancer progression and offer insights for further research on TET3 as a potential therapeutic target for pan-cancer.
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Affiliation(s)
- Chunyan Zhang
- Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, China
- Tianjin Key Laboratory of Epigenetics for Organ Development of Premature Infants, Tianjin Fifth Central Hospital, Tianjin, China
- High Altitude Characteristic Medical Research Institute, Huangnan Tibetan Autonomous Prefecture People’s Hospital, Huangnan Prefecture, Qinghai, China
| | - Jie Zheng
- Department of Pathology, Tianjin Fifth Central Hospital, Tianjin, China
| | - Jin Liu
- North China University of Science and Technology, Tangshan, Hebei, China
| | - Yanxia Li
- Tianjin Key Laboratory of Epigenetics for Organ Development of Premature Infants, Tianjin Fifth Central Hospital, Tianjin, China
- High Altitude Characteristic Medical Research Institute, Huangnan Tibetan Autonomous Prefecture People’s Hospital, Huangnan Prefecture, Qinghai, China
| | - Guoqiang Xing
- Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, China
| | - Shupeng Zhang
- Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, China
| | - Hekai Chen
- Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, China
| | - Jian Wang
- Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, China
| | - Zhijiang Shao
- Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, China
- High Altitude Characteristic Medical Research Institute, Huangnan Tibetan Autonomous Prefecture People’s Hospital, Huangnan Prefecture, Qinghai, China
| | - Yongyuan Li
- Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, China
- High Altitude Characteristic Medical Research Institute, Huangnan Tibetan Autonomous Prefecture People’s Hospital, Huangnan Prefecture, Qinghai, China
| | - Zhongmin Jiang
- Department of Pathology, Tianjin Fifth Central Hospital, Tianjin, China
| | - Yingzi Pan
- Department of Ophthalmology, Peking University First Hospital, Beijing, China
| | - Xiaozhi Liu
- Tianjin Key Laboratory of Epigenetics for Organ Development of Premature Infants, Tianjin Fifth Central Hospital, Tianjin, China
- High Altitude Characteristic Medical Research Institute, Huangnan Tibetan Autonomous Prefecture People’s Hospital, Huangnan Prefecture, Qinghai, China
| | - Ping Xu
- High Altitude Characteristic Medical Research Institute, Huangnan Tibetan Autonomous Prefecture People’s Hospital, Huangnan Prefecture, Qinghai, China
- Department of Pharmacy, Tianjin Fifth Central Hospital, Tianjin, China
| | - Wenhan Wu
- Department of General Surgery, Tianjin Fifth Central Hospital, Tianjin, China
- Tianjin Key Laboratory of Epigenetics for Organ Development of Premature Infants, Tianjin Fifth Central Hospital, Tianjin, China
- High Altitude Characteristic Medical Research Institute, Huangnan Tibetan Autonomous Prefecture People’s Hospital, Huangnan Prefecture, Qinghai, China
- Department of General Surgery, Peking University First Hospital, Beijing, China
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11
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Mafi A, Hedayati N, Milasi YE, Kahkesh S, Daviran M, Farahani N, Hashemi M, Nabavi N, Alimohammadi M, Rahimzadeh P, Taheriazam A. The function and mechanism of circRNAs in 5-fluorouracil resistance in tumors: Biological mechanisms and future potential. Pathol Res Pract 2024; 260:155457. [PMID: 39018926 DOI: 10.1016/j.prp.2024.155457] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 07/04/2024] [Accepted: 07/05/2024] [Indexed: 07/19/2024]
Abstract
5-Fluorouracil (5-FU) is a well-known chemotherapy drug extensively used in the treatment of breast cancer. It works by inhibiting cancer cell proliferation and inducing cell death through direct incorporation into DNA and RNA via thymidylate synthase (TS). Circular RNAs (circRNAs), a novel family of endogenous non-coding RNAs (ncRNAs) with limited protein-coding potential, contribute to 5-FU resistance. Their identification and targeting are crucial for enhancing chemosensitivity. CircRNAs can regulate tumor formation and invasion by adhering to microRNAs (miRNAs) and interacting with RNA-binding proteins, regulating transcription and translation. MiRNAs can influence enzymes responsible for 5-FU metabolism in cancer cells, affecting their sensitivity or resistance to the drug. In the context of 5-FU resistance, circRNAs can target miRNAs and regulate biological processes such as cell proliferation, cell death, glucose metabolism, hypoxia, epithelial-to-mesenchymal transition (EMT), and drug efflux. This review focuses on the function of circRNAs in 5-FU resistance, discussing the underlying molecular pathways and biological mechanisms. It also presents recent circRNA/miRNA-targeted cancer therapeutic strategies for future clinical application.
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Affiliation(s)
- Alireza Mafi
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Neda Hedayati
- School of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Yaser Eshaghi Milasi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Samaneh Kahkesh
- Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Minoo Daviran
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Najma Farahani
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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12
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Cayún JP, Cerpa LC, Colombo A, Cáceres DD, Leal JL, Reyes F, Gutiérrez-Cáceres C, Calfunao S, Varela NM, Quiñones LA. Genetic Polymorphisms and Tumoral Mutational Profiles over Survival in Advanced Colorectal Cancer Patients: An Exploratory Study. Curr Oncol 2024; 31:274-295. [PMID: 38248103 PMCID: PMC10814806 DOI: 10.3390/curroncol31010018] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/23/2023] [Accepted: 12/27/2023] [Indexed: 01/23/2024] Open
Abstract
Colorectal cancer is a common disease, both in Chile and worldwide. The most widely used chemotherapy schemes are based on 5-fluorouracil (5FU) as the foundational drug (FOLFOX, CapeOX). Genetic polymorphisms have emerged as potential predictive biomarkers of response to chemotherapy, but conclusive evidence is lacking. This study aimed to investigate the role of genetic variants associated with 5FU-based chemotherapy on therapeutic response, considering their interaction with oncogene mutations (KRAS, NRAS, PI3KCA, AKT1, BRAF). In a retrospective cohort of 63 patients diagnosed with metastatic colorectal cancer, a multivariate analysis revealed that liver metastases, DPYD, ABCB1, and MTHFR polymorphisms are independent indicators of poor prognosis, irrespective of oncogene mutations. BRAF wild-type status and high-risk drug-metabolism polymorphisms correlated with a poor prognosis in this Chilean cohort. Additionally, findings from the genomics of drug sensitivity (GDSC) project demonstrated that cell lines with wild-type BRAF have higher IC50 values for 5-FU compared to BRAF-mutated cell lines. In conclusion, the genetic polymorphisms DPYDrs1801265, ABCB1rs1045642, and MTHFRrs180113 may serve as useful biomarkers for predicting a poor prognosis in patients undergoing 5-fluorouracil chemotherapy, regardless of oncogene mutations.
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Affiliation(s)
- Juan Pablo Cayún
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (J.P.C.); (L.C.C.); (C.G.-C.); (S.C.)
- Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago 8350499, Chile
| | - Leslie Carol Cerpa
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (J.P.C.); (L.C.C.); (C.G.-C.); (S.C.)
- Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago 8350499, Chile
| | - Alicia Colombo
- Anatomy Pathology Service, Hospital Clínico de la Universidad de Chile, Santiago 8350499, Chile;
- Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago 8350499, Chile
| | - Dante Daniel Cáceres
- Institute of Population Health, School of Public Health, Faculty of Medicine, University of Chile, Santiago 8350499, Chile;
| | - José Luis Leal
- Cancer Research Department, Instituto Oncológico Fundación Arturo López Pérez, Santiago 8350499, Chile; (J.L.L.); (F.R.)
| | - Felipe Reyes
- Cancer Research Department, Instituto Oncológico Fundación Arturo López Pérez, Santiago 8350499, Chile; (J.L.L.); (F.R.)
| | - Carolina Gutiérrez-Cáceres
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (J.P.C.); (L.C.C.); (C.G.-C.); (S.C.)
- Department of Pharmaceutical Sciences and Technology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8350499, Chile
| | - Susan Calfunao
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (J.P.C.); (L.C.C.); (C.G.-C.); (S.C.)
- Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago 8350499, Chile
- Laboratory Pathological Anatomy, Hospital Luis Calvo Mackenna, Santiago 8350499, Chile
| | - Nelson Miguel Varela
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (J.P.C.); (L.C.C.); (C.G.-C.); (S.C.)
- Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago 8350499, Chile
| | - Luis Abel Quiñones
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (J.P.C.); (L.C.C.); (C.G.-C.); (S.C.)
- Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago 8350499, Chile
- Department of Pharmaceutical Sciences and Technology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8350499, Chile
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13
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Kusumaningrum AE, Makaba S, Ali E, Singh M, Fenjan MN, Rasulova I, Misra N, Al-Musawi SG, Alsalamy A. A perspective on emerging therapies in metastatic colorectal cancer: Focusing on molecular medicine and drug resistance. Cell Biochem Funct 2024; 42:e3906. [PMID: 38269502 DOI: 10.1002/cbf.3906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 11/23/2023] [Accepted: 12/01/2023] [Indexed: 01/26/2024]
Abstract
The majority of cancer cases are colorectal cancer, which is also the second largest cause of cancer-related deaths worldwide. Metastasis is the leading cause of death for patients with colorectal cancer. Metastatic colorectal cancer incidence are on the rise due to a tiny percentage of tumors developing resistant to medicines despite advances in treatment tactics. Cutting-edge targeted medications are now the go-to option for customized and all-encompassing CRC care. Specifically, multitarget kinase inhibitors, antivascular endothelial growth factors, and epidermal growth factor receptors are widely used in clinical practice for CRC-targeted treatments. Rare targets in metastatic colorectal cancer are becoming more well-known due to developments in precision diagnostics and the extensive use of second-generation sequencing technology. These targets include the KRAS mutation, the BRAF V600E mutation, the HER2 overexpression/amplification, and the MSI-H/dMMR. Incorporating certain medications into clinical trials has significantly increased patient survival rates, opening new avenues and bringing fresh viewpoints for treating metastatic colorectal cancer. These focused therapies change how cancer is treated, giving patients new hope and better results. These markers can significantly transform and individualize therapy regimens. They could open the door to precisely customized and more effective medicines, improving patient outcomes and quality of life. The fast-growing body of knowledge regarding the molecular biology of colorectal cancer and the latest developments in gene sequencing and molecular diagnostics are directly responsible for this advancement.
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Affiliation(s)
| | - Sarce Makaba
- Researcher and lecturer, Universitas Cenderawasih Jayapura, Jayapura, Indonesia
| | - Eyhab Ali
- College of Pharmacy, Al-Zahraa University for Women, Karbala, Iraq
| | - Mandeep Singh
- Directorate of Sports and Physical Education, University of Jammu, Jammu, India
| | - Mohammed N Fenjan
- College of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq
| | - Irodakhon Rasulova
- School of Humanities, Natural & Social Sciences, New Uzbekistan University, Tashkent, Uzbekistan
- Department of Public Health, Samarkand State Medical University, Samarkand, Uzbekistan
| | - Neeti Misra
- Department of Management, Uttaranchal Institute of Management, Uttaranchal University, Dehradun, India
| | - Sada G Al-Musawi
- College of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | - Ali Alsalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna, Iraq
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14
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Gazzillo A, Volponi C, Soldani C, Polidoro MA, Franceschini B, Lleo A, Bonavita E, Donadon M. Cellular Senescence in Liver Cancer: How Dying Cells Become "Zombie" Enemies. Biomedicines 2023; 12:26. [PMID: 38275386 PMCID: PMC10813254 DOI: 10.3390/biomedicines12010026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 12/15/2023] [Accepted: 12/19/2023] [Indexed: 01/27/2024] Open
Abstract
Liver cancer represents the fourth leading cause of cancer-associated death worldwide. The heterogeneity of its tumor microenvironment (TME) is a major contributing factor of metastasis, relapse, and drug resistance. Regrettably, late diagnosis makes most liver cancer patients ineligible for surgery, and the frequent failure of non-surgical therapeutic options orientates clinical research to the investigation of new drugs. In this context, cellular senescence has been recently shown to play a pivotal role in the progression of chronic inflammatory liver diseases, ultimately leading to cancer. Moreover, the stem-like state triggered by senescence has been associated with the emergence of drug-resistant, aggressive tumor clones. In recent years, an increasing number of studies have emerged to investigate senescence-associated hepatocarcinogenesis and its derived therapies, leading to promising results. In this review, we intend to provide an overview of the recent evidence that unveils the role of cellular senescence in the most frequent forms of primary and metastatic liver cancer, focusing on the involvement of this mechanism in therapy resistance.
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Affiliation(s)
- Aurora Gazzillo
- Cellular and Molecular Oncoimmunology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (A.G.); (C.V.); (E.B.)
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy;
| | - Camilla Volponi
- Cellular and Molecular Oncoimmunology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (A.G.); (C.V.); (E.B.)
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy;
| | - Cristiana Soldani
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (C.S.); (M.A.P.); (B.F.)
| | - Michela Anna Polidoro
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (C.S.); (M.A.P.); (B.F.)
| | - Barbara Franceschini
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (C.S.); (M.A.P.); (B.F.)
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy;
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (C.S.); (M.A.P.); (B.F.)
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
| | - Eduardo Bonavita
- Cellular and Molecular Oncoimmunology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (A.G.); (C.V.); (E.B.)
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy;
| | - Matteo Donadon
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (C.S.); (M.A.P.); (B.F.)
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy
- Department of General Surgery, University Maggiore Hospital della Carità, 28100 Novara, Italy
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Mangieri CW, Valenzuela CD, Solsky IB, Erali RA, Votanopoulos KI, Shen P, Levine EA. Exposure to Neoadjuvant Oxaliplatin-Containing Chemotherapy, Does it Effect Intraperitoneal Hyperthermic Chemotherapy Perfusion? Ann Surg Oncol 2023; 30:2486-2493. [PMID: 36484904 DOI: 10.1245/s10434-022-12933-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 11/21/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) are commonly exposed to oxaliplatin neoadjuvant chemotherapy (NAT) regimens. The impact of systemic exposure to oxaliplatin prior to HIPEC with oxaliplatin is unknown. METHODS We conducted a retrospective review of our institutional registry of CRS/HIPEC cases who received oxaliplatin-containing NAT, and compared patients who underwent HIPEC with oxaliplatin versus cases perfused with mitomycin C. The primary outcome was survival, defined by overall survival (OS) and disease-free survival (DFS). Subgroup analysis was performed based on primary tumor etiology and completeness of cytoreduction. RESULTS A total of 333 cases satisfied the selection criteria-159 appendiceal primaries (all high-grade disease) and 174 colorectal cases. Thirty-one cases (9.3%) underwent HIPEC with oxaliplatin, with the remaining 302 cases (90.7%) receiving mitomycin C. Both cohorts were identical in regard to baseline characteristics, and both groups were alike in regard to NAT regimens and oxaliplatin exposure. There was no difference in survival outcomes. OS times were 2.9 (± 2.8) and 2.8 ( ± 3.6) years for oxaliplatin and mitomycin C perfusions, respectively (p = 0.94), and the 5-year OS rates were also similar at 9.7 and 18.5% (odds ratio [OR] 0.49, 95% confidence interval [CI] 0.14-1.67, p = 0.24) for oxaliplatin and mitomycin cases, respectively. Likewise, DFS findings were similar, with survival of 2.5 (± 4.5) and 1.8 (± 2.4) years for oxaliplatin and mitomycin perfusions, respectively (p = 0.21). There was no difference in 5-year DFS rates, at 10.5 and 7.8% (OR 1.39, 95% CI 0.30-6.56, p = 0.68) for oxaliplatin and mitomycin C, respectively. Subgroup analysis found minimal discordant findings from the main results. CONCLUSION This analysis found no discernable association with NAT oxaliplatin exposure in regard to survival outcomes following CRS/HIPEC stratified out by perfusion agent.
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Affiliation(s)
- Christopher W Mangieri
- Division of Surgical Oncology, Wake Forest Baptist Health Medical Center, Winston-Salem, NC, USA
| | - Cristian D Valenzuela
- Division of Surgical Oncology, Wake Forest Baptist Health Medical Center, Winston-Salem, NC, USA
| | - Ian B Solsky
- Division of Surgical Oncology, Wake Forest Baptist Health Medical Center, Winston-Salem, NC, USA
| | - Richard A Erali
- Division of Surgical Oncology, Wake Forest Baptist Health Medical Center, Winston-Salem, NC, USA
| | | | - Perry Shen
- Division of Surgical Oncology, Wake Forest Baptist Health Medical Center, Winston-Salem, NC, USA
| | - Edward A Levine
- Division of Surgical Oncology, Wake Forest Baptist Health Medical Center, Winston-Salem, NC, USA.
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16
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Yang J, He C, Liu N. Proteomic analysis of the chemosensitizing effect of curcumin on CRC cells treated with 5-FU. Front Med (Lausanne) 2022; 9:1032256. [PMID: 36507511 PMCID: PMC9729741 DOI: 10.3389/fmed.2022.1032256] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/02/2022] [Indexed: 11/25/2022] Open
Abstract
Background 5-Fluorouracil (5-FU) is one of the most common chemotherapy drugs used to treat colorectal cancer (CRC), which often develops resistance in more than 15% of patients. Curcumin, an active component of Curcuma longa, has been reported to show antitumor activity in CRC and, furthermore, enhance the effect of chemotherapy against colorectal cancer cells. However, the molecular mechanisms underlying the sensitizing effect of curcumin on 5-FU have not been largely elucidated. In this study, we aimed to systematically investigate the role of curcumin as a chemosensitizer for the treatment of CRC, along with the key events responsible for its pharmaceutical effect, which may lead to better clinical outcomes. Methods A high-resolution 2DE-based proteomics approach was used to characterize global protein expression patterns in CRC cells treated with 5-FU both in combination with curcumin or without. The differentially expressed proteins were obtained from the 2DE analysis and subsequently identified by MALDI-TOF MS or nano-ESI-MS/MS, some of which were validated by the Western blot. Intracellular reactive oxygen species (ROS) were measured to assess the change in the redox environment resulting from the drug treatment. Results A series of proteins with altered abundances were detected and identified by MALDI-TOF or nano-MS/MS. From a total of 512 isolated proteins, 22 proteins were found to be upregulated and 6 proteins were downregulated. Intracellular ROS was significantly elevated after curcumin treatment. Furthermore, mass spectrometry data revealed that some of the proteins appeared to have more oxidized forms upon curcumin treatment, suggesting a direct role for ROS in the chemosensitizing effect of curcumin. Conclusion The effect of curcumin in enhancing chemosensitivity to 5-FU is a complex phenomenon made up of several mechanisms, including enhancement of the intracellular level of ROS. Our findings presented here could provide clues for a further study aimed at elucidating the mechanisms underlying the chemosensitizing effect of curcumin.
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Affiliation(s)
- Jingbo Yang
- Central Laboratory, Second Hospital, Jilin University, Changchun, China
| | - Chengyan He
- Clinical Laboratory, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Ning Liu
- Central Laboratory, Second Hospital, Jilin University, Changchun, China,*Correspondence: Ning Liu
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17
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Luo D, Liu X, Jiang L, Guo Z, Lv Y, Tian X, Wang X, Cui S, Wan S, Qu X, Xu X, Li X. Rational Design, Synthesis, and Biological Evaluation of Novel S1PR2 Antagonists for Reversing 5-FU-Resistance in Colorectal Cancer. J Med Chem 2022; 65:14553-14577. [PMID: 36269639 DOI: 10.1021/acs.jmedchem.2c00958] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Resistance to 5-FU reduces its clinical efficacy for the treatment of colorectal cancer. Sphingosine-1-phosphate receptor 2 (S1PR2) has emerged as a potential target to reverse 5-FU-resistance by inhibiting the expression of dihydropyrimidine dehydrogenase (DPD). In this study, 38 novel S1PR2 antagonists based on aryl urea structure were designed and synthesized, and the structure-activity relationship was investigated based on the S1PR2 binding assay. Representative compound 43 potently interacts with S1PR2 with a KD value of 0.73 nM. It displays potent 5-FU resensitizing activity in multiple 5-FU-resistant tumor cell lines, particularly in SW620/5-FU (EC50 = 1.99 ± 0.03 μM) but shows no cytotoxicity in the normal colon cell line NCM460 up to 1000 μM. Moreover, 43 significantly enhances the antitumor efficacy of 5-FU in the SW620/5-FU animal model. These data suggest that 43 could be a novel lead compound for developing a 5-FU resensitizing agent.
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Affiliation(s)
- Dongdong Luo
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China
| | - Xiaochun Liu
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China
| | - Leilei Jiang
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China
| | - Zhikun Guo
- Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, 100069 Beijing, China
| | - Yan Lv
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China
| | - Xiaochen Tian
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China
| | - Xiaoyan Wang
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China
| | - Shuxiang Cui
- Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, 100069 Beijing, China
| | - Shengbiao Wan
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China
| | - Xianjun Qu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, 100069 Beijing, China
| | - Ximing Xu
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China
| | - Xiaoyang Li
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China
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Disulfiram increases the efficacy of 5-fluorouracil in organotypic cultures of colorectal carcinoma. Biomed Pharmacother 2022; 153:113465. [DOI: 10.1016/j.biopha.2022.113465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 11/20/2022] Open
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19
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Huang CZ, Zhou Y, Tong QS, Duan QJ, Zhang Q, Du JZ, Yao XQ. Precision medicine-guided co-delivery of ASPN siRNA and oxaliplatin by nanoparticles to overcome chemoresistance of colorectal cancer. Biomaterials 2022; 290:121827. [DOI: 10.1016/j.biomaterials.2022.121827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 09/18/2022] [Accepted: 09/24/2022] [Indexed: 11/02/2022]
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20
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Zdesenko G, Mduluza T, Mutapi F. Pharmacogenetics of Praziquantel Metabolism: Evaluating the Cytochrome P450 Genes of Zimbabwean Patients During a Schistosomiasis Treatment. Front Genet 2022; 13:914372. [PMID: 35754834 PMCID: PMC9213834 DOI: 10.3389/fgene.2022.914372] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 05/17/2022] [Indexed: 11/13/2022] Open
Abstract
Schistosomiasis is a parasitic disease infecting over 236 million people annually, with the majority affected residing on the African continent. Control of this disease is reliant on the drug praziquantel (PZQ), with treatment success dependent on an individual reaching PZQ concentrations lethal to schistosomes. Despite the complete reliance on PZQ to treat schistosomiasis in Africa, the characterization of the pharmacogenetics associated with PZQ metabolism in African populations has been sparse. We aimed to characterize genetic variation in the drug-metabolising cytochrome P450 enzymes (CYPs) and determine the association between each variant and the efficacy of PZQ treatment in Zimbabwean patients exposed to Schistosoma haematobium infection. Genomic DNA from blood samples of 114 case-control Zimbabweans infected with schistosomes were sequenced using the CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 genes as targets. Bioinformatic tools were used to identify and predict functional effects of detected single nucleotide polymorphisms (SNPs). A random forest (RF) model was then used to assess SNPs most predictive of PZQ efficacy, with a misclassification rate of 29%. SNPs were detected across all six genes, with 70 SNPs identified and multiple functional changes to the CYP enzymes predicted. Only four SNPs were significantly associated with PZQ efficacy using χ2 tests, with rs951840747 (OR: 3.61, p = 0.01) in the CYP1A2 gene having the highest odds of an individual possessing this SNP clearing infection, and rs6976017 (OR: 2.19, p = 0.045) of CYP3A5 determined to be the most predictive of PZQ efficacy via the RF. Only the rs28371702 (CC) genotype (OR: 2.36, p = 0.024) of CYP2D6 was significantly associated with an unsuccessful PZQ treatment. This study adds to the genomic characterization of the diverse populations in Africa and identifies variants relevant to other pharmacogenetic studies crucial for the development and usage of drugs in these populations.
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Affiliation(s)
- Grace Zdesenko
- Ashworth Laboratories, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.,Ashworth Laboratories, NIHR Global Health Research Unit Tackling Infections to Benefit Africa (TIBA), University of Edinburgh, Edinburgh, United Kingdom
| | - Takafira Mduluza
- Ashworth Laboratories, NIHR Global Health Research Unit Tackling Infections to Benefit Africa (TIBA), University of Edinburgh, Edinburgh, United Kingdom.,Department of Biochemistry, University of Zimbabwe, Harare, Zimbabwe
| | - Francisca Mutapi
- Ashworth Laboratories, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.,Ashworth Laboratories, NIHR Global Health Research Unit Tackling Infections to Benefit Africa (TIBA), University of Edinburgh, Edinburgh, United Kingdom
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Huang X, Ke K, Jin W, Zhu Q, Zhu Q, Mei R, Zhang R, Yu S, Shou L, Sun X, Feng J, Duan T, Mou Y, Xie T, Wu Q, Sui X. Identification of Genes Related to 5-Fluorouracil Based Chemotherapy for Colorectal Cancer. Front Immunol 2022; 13:887048. [PMID: 35784334 PMCID: PMC9247273 DOI: 10.3389/fimmu.2022.887048] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/16/2022] [Indexed: 12/22/2022] Open
Abstract
Background Colorectal cancer (CRC) is one of the most common malignancies and its incidence and mortality are increasing yearly. 5-Fluorouracil (5-FU) has long been used as a standard first-line treatment for CRC patients. Although 5-FU-based chemotherapy is effective for advanced CRC, the consequent resistance remains a key problem and causes the poor prognosis of CRC patients. Thus, there is an urgent need to identify new biomarkers to predict the response to 5-FU-based chemotherapy. Methods CRC samples were retrieved from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). The immune-related genes were retrieved from the ImmPort database. Single-cell sequencing results from colorectal cancer were obtained by the ArrayExpress database. 5-FU resistance-related genes were filtered and validated by R packages. ESTIMATE algorithms were used to assess the tumor microenvironment (TME). KEGG and GO analysis were performed to explore the biological signaling pathway for resistant-response patients and sensitive-response patients in the tumor microenvironment. pRRophetic algorithms were used to predict 5-FU sensitivity. GSEA and GSVA analysis was performed to excavate the biological signaling pathway of the RBP7 gene. Results Nine immune-related genes were identified to be associated with 5-FU resistance and poor disease-free survival (DFS) of CRC patients and the signature of these genes was developed in a DFS-prognostic model. Four immune-related genes were determined to be associated with 5-FU resistance and overall survival (OS) of CRC patients. The signature of these genes was developed an OS-prognostic model. ESTIMATE scores showed a significant difference between 5-FU resistant and 5-FU sensitive CRC patients. Resistant-response patients and sensitive-response patients to 5-FU based chemotherapy showed different GO and KEGG enrichment on the tumor microenvironment. RBP7, as a tumor immune microenvironment (TIME) related gene, was found to have the potential of predicting chemotherapy resistance and poor prognosis of CRC patients. GSEA analysis showed multiple signaling differences between the high and low expression of RBP7 in CRC patients. Hypoxia and TNFα signaling via NFκB gene sets were significantly different between chemotherapy resistant (RBP7High) and chemotherapy sensitive (RBP7Low) patients. Single-cell RNA-seq suggested RBP7 was centrally distributed in endothelial stalk cells, endothelial tip cells, and myeloid cells. Conclusions Immune-related genes will hopefully be potential prognostic biomarkers to predict chemotherapy resistance for CRC. RBP7 may function as a tumor microenvironment regulator to induce 5-FU resistance, thereby affecting the prognosis of CRC patients.
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Affiliation(s)
- Xingxing Huang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, Macau SAR, China
- School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Kun Ke
- Department of Gastrointestinal-Pancreatic Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Weiwei Jin
- Department of Gastrointestinal-Pancreatic Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Qianru Zhu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, Macau SAR, China
- School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Qicong Zhu
- Department of Gastrointestinal-Pancreatic Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Ruyi Mei
- School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Ruonan Zhang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, Macau SAR, China
- School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Shuxian Yu
- School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Lan Shou
- School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Xueni Sun
- School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Jiao Feng
- School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Ting Duan
- School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Yiping Mou
- Department of Gastrointestinal-Pancreatic Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
- *Correspondence: Yiping Mou, ; Tian Xie, ; Qibiao Wu, ; Xinbing Sui,
| | - Tian Xie
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, Macau SAR, China
- School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
- *Correspondence: Yiping Mou, ; Tian Xie, ; Qibiao Wu, ; Xinbing Sui,
| | - Qibiao Wu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, Macau SAR, China
- School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Guangdong-Hong Kong-Macau Joint Laboratory for Contaminants Exposure and Health, Guangzhou, China
- *Correspondence: Yiping Mou, ; Tian Xie, ; Qibiao Wu, ; Xinbing Sui,
| | - Xinbing Sui
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, Macau SAR, China
- School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
- *Correspondence: Yiping Mou, ; Tian Xie, ; Qibiao Wu, ; Xinbing Sui,
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Alhazzani K, Venkatesan T, Natarajan U, Algahtani M, Alaseem A, Alobid S, Rathinavelu A. Evaluation of antitumor effects of VEGFR-2 inhibitor F16 in a colorectal xenograft model. Biotechnol Lett 2022; 44:787-801. [PMID: 35501620 DOI: 10.1007/s10529-022-03243-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 03/04/2022] [Indexed: 11/02/2022]
Abstract
OBJECTIVES Colorectal cancer (CRC) is the third most prevalent type of cancer in the United States. The treatment options for cancer include surgery, chemotherapy, radiation, and/or targeted therapy, which show significant improvement in overall survival. Among the various available treatments, antagonizing VEGF/VEGFR-2 pathways have shown effectiveness in limiting colorectal cancer growth and improving clinical outcomes. In this regard, we hypothesized that F16, a novel VEGFR-2 inhibitor, would control colorectal cancer growth by blocking the VEGFR-2 singling pathway in both in vitro and in vivo conditions. Therefore, the current study was aimed to analyze the efficacy of F16 on the growth of Colo 320DM cells under in vitro and in vivo conditions. RESULTS Human RT2 profiler PCR array analysis results clearly showed that angiogenesis and anti-apoptosis-related gene expressions were significantly reduced in HUVEC cells after F16 (5 μM) treatment. In addition, Western blot results revealed that F16 attenuated the downstream signaling of the VEGFR-2 pathway in HUVEC cells by up-regulating the p53 and p21 levels and down-regulating the p-AKT and p-FAK levels. Accordingly, F16 confirmed potent cytotoxic effects against the cell viability of Colo 320DM tumors, with an IC50 value of 9.52 ± 1.49 µM. Furthermore, treatment of mice implanted with Colo 320DM xenograft tumors showed a significant reduction in tumor growth and increases in survival rate compared to controls. Immunohistochemistry analysis of tumor tissues showed a reduction in CD31 levels also in F16 treated groups. CONCLUSIONS These results justify further evaluation of F16 as a potential new therapeutic agent for treating colorectal cancers.
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Affiliation(s)
- Khalid Alhazzani
- Pharmacology and Toxicology Department, College of Pharmacy, King Saud University, Riyadh, 12371, Saudi Arabia
| | - Thiagarajan Venkatesan
- Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, 3321 College Ave., Fort Lauderdale, FL, 33314, USA
| | - Umamaheswari Natarajan
- Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, 3321 College Ave., Fort Lauderdale, FL, 33314, USA
| | - Mohammad Algahtani
- Pharmacology and Toxicology Department, College of Pharmacy, King Saud University, Riyadh, 12371, Saudi Arabia
| | - Ali Alaseem
- College of Medicine, Al-Imam Mohammad Ibn Saud Islamic University, Riyadh, 13317, Saudi Arabia
| | - Saad Alobid
- Pharmacology and Toxicology Department, College of Pharmacy, King Saud University, Riyadh, 12371, Saudi Arabia
| | - Appu Rathinavelu
- Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, 3321 College Ave., Fort Lauderdale, FL, 33314, USA. .,College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, 33314, USA.
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Moutabian H, Majdaeen M, Ghahramani-Asl R, Yadollahi M, Gharepapagh E, Ataei G, Falahatpour Z, Bagheri H, Farhood B. A systematic review of the therapeutic effects of resveratrol in combination with 5-fluorouracil during colorectal cancer treatment: with a special focus on the oxidant, apoptotic, and anti-inflammatory activities. Cancer Cell Int 2022; 22:142. [PMID: 35366874 PMCID: PMC8976963 DOI: 10.1186/s12935-022-02561-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 03/27/2022] [Indexed: 12/24/2022] Open
Abstract
PURPOSE 5-fluorouracil (5-FU), an effective chemotherapy drug, is commonly applied for colorectal cancer treatment. Nevertheless, its toxicity to normal tissues and the development of tumor resistance are the main obstacles to successful cancer chemotherapy and hence, its clinical application is limited. The use of resveratrol can increase 5-FU-induced cytotoxicity and mitigate the unwanted adverse effects. This study aimed to review the potential therapeutic effects of resveratrol in combination with 5-FU against colorectal cancer. METHODS According to the PRISMA guideline, a comprehensive systematic search was carried out for the identification of relevant literature in four electronic databases of PubMed, Web of Science, Embase, and Scopus up to May 2021 using a pre-defined set of keywords in their titles and abstracts. We screened 282 studies in accordance with our inclusion and exclusion criteria. Thirteen articles were finally included in this systematic review. RESULTS The in vitro findings showed that proliferation inhibition of colorectal cancer cells in the groups treated by 5-FU was remarkably higher than the untreated groups and the co-administration of resveratrol remarkably increased cytotoxicity induced by 5-FU. The in vivo results demonstrated a decrease in tumor growth of mice treated by 5-FU than the untreated group and a dramatic decrease was observed following combined treatment of resveratrol and 5-FU. It was also found that 5-FU alone and combined with resveratrol could regulate the cell cycle profile of colorectal cancer cells. Moreover, this chemotherapeutic agent induced the biochemical and histopathological changes in the cancerous cells/tissues and these alterations were synergized by resveratrol co-administration (for most of the cases), except for the inflammatory mediators. CONCLUSION The results obtained from this systematic review demonstrated that co-administration of resveratrol could sensitize the colorectal cancer cells to 5-FU treatment via various mechanisms, including regulation of cell cycle distribution, oxidant, apoptosis, anti-inflammatory effects.
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Affiliation(s)
- Hossein Moutabian
- Radiation Sciences Research Center (RSRC), AJA University of Medical Sciences, Tehran, Iran
| | - Mehrsa Majdaeen
- Department of Radiotherapy and Oncology, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Ruhollah Ghahramani-Asl
- Department of Medical Physics and Radiological Sciences, Faculty of Paramedicine, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Masoumeh Yadollahi
- Department of Allied Medical Sciences, Semnan University of Medical Sciences, Semnan, Iran
| | - Esmaeil Gharepapagh
- Medical Radiation Sciences Research Team, Tabriz University of Medical Science, Tabriz, Iran
| | - Gholamreza Ataei
- Department of Radiology Technology, Faculty of Paramedical Sciences, Babol University of Medical Sciences, Babol, Iran
| | - Zahra Falahatpour
- Department of Medical Physics, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Bagheri
- Radiation Sciences Research Center (RSRC), AJA University of Medical Sciences, Tehran, Iran.
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Bagher Farhood
- Trauma Research Center, Kashan University of Medical Sciences, Kashan, Iran.
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Islam MR, Awal MA, Khames A, Abourehab MAS, Samad A, Hassan WMI, Alam R, Osman OI, Nur SM, Molla MHR, Abdulrahman AO, Rajia S, Ahammad F, Hasan MN, Qadri I, Kim B. Computational Identification of Druggable Bioactive Compounds from Catharanthus roseus and Avicennia marina against Colorectal Cancer by Targeting Thymidylate Synthase. Molecules 2022; 27:2089. [PMID: 35408488 PMCID: PMC9000506 DOI: 10.3390/molecules27072089] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 02/20/2022] [Accepted: 02/25/2022] [Indexed: 01/05/2023] Open
Abstract
Colorectal cancer (CRC) is the second most common cause of death worldwide, affecting approximately 1.9 million individuals in 2020. Therapeutics of the disease are not yet available and discovering a novel anticancer drug candidate against the disease is an urgent need. Thymidylate synthase (TS) is an important enzyme and prime precursor for DNA biosynthesis that catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) that has emerged as a novel drug target against the disease. Elevated expression of TS in proliferating cells promotes oncogenesis as well as CRC. Therefore, this study aimed to identify potential natural anticancer agents that can inhibit the activity of the TS protein, subsequently blocking the progression of colorectal cancer. Initially, molecular docking was implied on 63 natural compounds identified from Catharanthus roseus and Avicennia marina to evaluate their binding affinity to the desired protein. Subsequently, molecular dynamics (MD) simulation, ADME (Absorption, Distribution, Metabolism, and Excretion), toxicity, and quantum chemical-based DFT (density-functional theory) approaches were applied to evaluate the efficacy of the selected compounds. Molecular docking analysis initially identified four compounds (PubChem CID: 5281349, CID: 102004710, CID: 11969465, CID: 198912) that have better binding affinity to the target protein. The ADME and toxicity properties indicated good pharmacokinetics (PK) and toxicity ability of the selected compounds. Additionally, the quantum chemical calculation of the selected molecules found low chemical reactivity indicating the bioactivity of the drug candidate. The global descriptor and HOMO-LUMO energy gap values indicated a satisfactory and remarkable profile of the selected molecules. Furthermore, MD simulations of the compounds identified better binding stability of the compounds to the desired protein. To sum up, the phytoconstituents from two plants showed better anticancer activity against TS protein that can be further developed as an anti-CRC drug.
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Affiliation(s)
- Md Rashedul Islam
- Department of Chemistry, Faculty of Science, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia; (M.R.I.); (W.M.I.H.); (O.I.O.)
- Department of Pharmacy, Faculty of Life and Earth Sciences, Jagannath University, Dhaka 1100, Bangladesh
- Department of Pharmacy, Varendra University, Rajshahi 6204, Bangladesh;
| | - Md Abdul Awal
- Department of Biochemistry, Faculty of Science, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia; (M.A.A.); (S.M.N.); (A.O.A.)
| | - Ahmed Khames
- Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;
| | - Mohammad A. S. Abourehab
- Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia;
- Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Minia University, Minia 61519, Egypt
| | - Abdus Samad
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore 7408, Bangladesh; (A.S.); (R.A.)
- Laboratory of Computational Biology, Biological Solution Centre (BioSol Centre), Jashore 7408, Bangladesh
| | - Walid M. I. Hassan
- Department of Chemistry, Faculty of Science, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia; (M.R.I.); (W.M.I.H.); (O.I.O.)
| | - Rahat Alam
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore 7408, Bangladesh; (A.S.); (R.A.)
- Laboratory of Computational Biology, Biological Solution Centre (BioSol Centre), Jashore 7408, Bangladesh
| | - Osman I. Osman
- Department of Chemistry, Faculty of Science, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia; (M.R.I.); (W.M.I.H.); (O.I.O.)
| | - Suza Mohammad Nur
- Department of Biochemistry, Faculty of Science, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia; (M.A.A.); (S.M.N.); (A.O.A.)
| | | | - Abdulrasheed O. Abdulrahman
- Department of Biochemistry, Faculty of Science, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia; (M.A.A.); (S.M.N.); (A.O.A.)
- Institut Cochin, Université de Paris, Inserm, 75014 Paris, France
| | - Sultana Rajia
- Department of Pharmacy, Varendra University, Rajshahi 6204, Bangladesh;
- Center for Interdisciplinary Research (CIR), Varendra University, Rajshahi 6204, Bangladesh
| | - Foysal Ahammad
- Laboratory of Computational Biology, Biological Solution Centre (BioSol Centre), Jashore 7408, Bangladesh
- Department of Biological Sciences, Faculty of Science, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia;
| | - Md Nazmul Hasan
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore 7408, Bangladesh; (A.S.); (R.A.)
- Laboratory of Pharmaceutical Biotechnology and Bioinformatics, Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore 7408, Bangladesh
| | - Ishtiaq Qadri
- Department of Biological Sciences, Faculty of Science, King Abdul-Aziz University, Jeddah 21589, Saudi Arabia;
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
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TIMP-2 regulates 5-Fu resistance via the ERK/MAPK signaling pathway in colorectal cancer. Aging (Albany NY) 2022; 14:297-315. [PMID: 35022331 PMCID: PMC8791226 DOI: 10.18632/aging.203793] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 12/03/2021] [Indexed: 12/24/2022]
Abstract
5-Fluorouracil (5-Fu) is the first-line chemotherapeutic option for colorectal cancer. However, its efficacy is inhibited by drug resistance. Cytokines play an important role in tumor drug resistance, even though their mechanisms are largely unknown. Using a cytokine array, we established that tissue inhibitor metalloproteinase 2 (TIMP-2) is highly expressed in 5-Fu resistant colorectal cancer patients. Analysis of samples from 84 patients showed that elevated TIMP-2 expression levels in colorectal patients were correlated with poor prognostic outcomes. In a 5-Fu-resistant patient-derived xenograft (PDX) model, TIMP-2 was also found to be highly expressed. We established an autocrine mechanism through which elevated TIMP-2 protein levels sustained colorectal cancer cell resistance to 5-Fu by constitutively activating the ERK/MAPK signaling pathway. Inhibition of TIMP-2 using an anti-TIMP-2 antibody or ERK/MAPK inhibition by U0126 suppressed TIMP-2 mediated 5-Fu-resistance in CRC patients. In conclusion, a novel TIMP-2-ERK/MAPK mediated 5-Fu resistance mechanism is involved in colorectal cancer. Therefore, targeting TIMP-2 or ERK/MAPK may provide a new strategy to overcome 5-Fu resistance in colorectal cancer chemotherapy.
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He X, Tang J, Yan HZ, Wang JX, Li HQ, Duan XW, Yu SY, Hou XL, Liao GB, Liu W. Anemoside B4 sensitizes human colorectal cancer to fluorouracil-based chemotherapy through src-mediated cell apoptosis. Aging (Albany NY) 2021; 13:25365-25376. [PMID: 34890366 PMCID: PMC8714157 DOI: 10.18632/aging.203751] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 08/11/2021] [Indexed: 02/07/2023]
Abstract
Currently, 5-Fluorouracil (5-FU) based chemotherapy is the primary option for colorectal cancer after surgery, whereas chemotherapy resistance related mortality is observed in a large proportion of patients. Anemoside B4 (AB4) is a triterpene saponin, which exhibits a considerable activity in oncotherapy. In this study, we explored the efficacy of AB4 in FU-based chemotherapy in colorectal cancer cells and the underlying molecular mechanisms. Our results indicated a significant synergistic activity of AB4 in 5-FU treated colorectal cancer cells. Furthermore, AB4 treatment eliminated colorectal cancer stem cells by promoting apoptotic cell death in 5-FU resistant colorectal cancer cells. Mechanically, AB4 activated caspase-9 pathway in 5-FU resistant colorectal cancer cells. Elevated Src activity induced cell apoptosis and cancer stem cells elimination effects in AB4 treated colorectal cancer cells. In conclusion, AB4 showed promising sensitization effect in the FU-based chemotherapy of colorectal cancer. Our study may pave a way to ameliorate FU-based chemotherapeutic efficiency in colorectal cancer.
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Affiliation(s)
- Xing He
- Department of Gastroenterology, The 901 Hospital of Joint Logistics Support Force, Hefei 230031, Anhui, China
| | - Jun Tang
- Department of Gastroenterology, The 901 Hospital of Joint Logistics Support Force, Hefei 230031, Anhui, China
| | - He-Zhong Yan
- Department of Gastroenterology, The 901 Hospital of Joint Logistics Support Force, Hefei 230031, Anhui, China
| | - Jiao-Xue Wang
- Department of Gastroenterology, The 901 Hospital of Joint Logistics Support Force, Hefei 230031, Anhui, China
| | - Hai-Qing Li
- Department of Gastroenterology, The 901 Hospital of Joint Logistics Support Force, Hefei 230031, Anhui, China
| | - Xiao-Wei Duan
- Department of Gastroenterology, The 901 Hospital of Joint Logistics Support Force, Hefei 230031, Anhui, China
| | - Sen-Yuan Yu
- Department of Gastroenterology, The 901 Hospital of Joint Logistics Support Force, Hefei 230031, Anhui, China
| | - Xi-Lu Hou
- Department of Gastroenterology, The 901 Hospital of Joint Logistics Support Force, Hefei 230031, Anhui, China
| | - Guo-Bin Liao
- Department of Gastroenterology, The 901 Hospital of Joint Logistics Support Force, Hefei 230031, Anhui, China
| | - Wei Liu
- Department of Gastroenterology, The 901 Hospital of Joint Logistics Support Force, Hefei 230031, Anhui, China
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27
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Luo D, Zhang Y, Yang S, Tian X, Lv Y, Guo Z, Liu X, Han G, Liu S, Wang W, Cui S, Qu X, Wan S. Design, synthesis and biological evaluation of sphingosine-1-phosphate receptor 2 antagonists as potent 5-FU-resistance reversal agents for the treatment of colorectal cancer. Eur J Med Chem 2021; 225:113775. [PMID: 34411894 DOI: 10.1016/j.ejmech.2021.113775] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/27/2021] [Accepted: 08/11/2021] [Indexed: 02/07/2023]
Abstract
5-Fluorouracil (5-FU) and its prodrugs are the essential clinical drugs for colorectal cancer (CRC) treatment. However, the drug resistance of 5-FU has caused high mortality of CRC patients. Thus, it is urgent to develop reversal agents of 5-FU resistance. Sphingosine-1-phosphate receptor 2 (S1PR2) was proved to be a potential target for reversing 5-FU resistance, but the activity of known S1PR2 antagonists JTE-013 were weak in 5-FU-resistant cell lines. To develop more potent S1PR2 antagonists to treat 5-FU-resistant cancer, a series of JTE-013 derivatives were designed and synthesized. The most promising compound 40 could markedly reverse the resistance in 5-FU-resistant HCT116 cells and 5-FU-resistant SW620 cells via inhibiting the expression of dihydropyrimidine dehydrogenase (DPD). The key was that compound 40 with improved pharmacokinetic properties significantly increased the inhibitory rate of 5-FU in the SW620/5-FU cells xenograft model with no observable toxicity by inhibiting the expression of DPD in tumor and liver tissues. Altogether, these results suggest that compound 40 may be a promising drug candidate to reverse 5-FU resistance in the treatment of CRC.
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Affiliation(s)
- Dongdong Luo
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Yuhang Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, 100034, China
| | - Shuang Yang
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Xiaochen Tian
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Yan Lv
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Zhikun Guo
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China
| | - Xiaochun Liu
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Gaitian Han
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Shuai Liu
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Wenyu Wang
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Shuxiang Cui
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China
| | - Xianjun Qu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
| | - Shengbiao Wan
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
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28
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Cordova-Delgado M, Bravo ML, Cumsille E, Hill CN, Muñoz-Medel M, Pinto MP, Retamal IN, Lavanderos MA, Miquel JF, Rodriguez-Fernandez M, Liao Y, Li Z, Corvalán AH, Armisén R, Garrido M, Quiñones LA, Owen GI. A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer. BMC Cancer 2021; 21:1030. [PMID: 34525956 PMCID: PMC8444616 DOI: 10.1186/s12885-021-08745-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 08/22/2021] [Indexed: 12/22/2022] Open
Abstract
Background Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3–4 toxicity. Methods Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. Results Reported grade ≤ 2 and 3–4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70–10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19–1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. Conclusion Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08745-0.
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Affiliation(s)
- Miguel Cordova-Delgado
- Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, 8380494, Santiago, Chile.,Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile.,Department of Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, 8330032, Santiago, Chile
| | - María Loreto Bravo
- Department of Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, 8330032, Santiago, Chile
| | - Elisa Cumsille
- Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile
| | - Charlotte N Hill
- Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, 8331150, Santiago, Chile
| | - Matías Muñoz-Medel
- Department of Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, 8330032, Santiago, Chile
| | - Mauricio P Pinto
- Department of Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, 8330032, Santiago, Chile
| | - Ignacio N Retamal
- Faculty of Dentistry, Universidad de Los Andes, 7620001, Santiago, Chile
| | - María A Lavanderos
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic and Clinical Oncology, Faculty of Medicine, Universidad de Chile, 8380494, Santiago, Chile.,Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Madrid, Spain.,Escuela de Química y Farmacia, Facultad de Ciencias Médicas, Universidad Bernardo O'Higgins, Santiago, Chile
| | - Juan Francisco Miquel
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, 8330032, Santiago, Chile
| | - Maria Rodriguez-Fernandez
- Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Yuwei Liao
- Central Laboratory, Yangjiang People's Hospital, GuangDong Province, Yangjiang, China.,Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Zhiguang Li
- Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.,National Institute on Aging, National Institute of Health, Baltimore, USA
| | - Alejandro H Corvalán
- Department of Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, 8330032, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), 8330034, Santiago, Chile
| | - Ricardo Armisén
- Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica Alemana, Universidad del Desarrollo, 7590943, Santiago, Chile
| | - Marcelo Garrido
- Department of Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, 8330032, Santiago, Chile
| | - Luis A Quiñones
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic and Clinical Oncology, Faculty of Medicine, Universidad de Chile, 8380494, Santiago, Chile. .,Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Madrid, Spain.
| | - Gareth I Owen
- Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile. .,Department of Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, 8330032, Santiago, Chile. .,Millennium Institute on Immunology and Immunotherapy, 8331150, Santiago, Chile. .,Advanced Center for Chronic Diseases (ACCDiS), 8330034, Santiago, Chile.
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29
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Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor. Int J Mol Sci 2021; 22:ijms22147330. [PMID: 34298950 PMCID: PMC8303674 DOI: 10.3390/ijms22147330] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/04/2021] [Accepted: 07/06/2021] [Indexed: 12/11/2022] Open
Abstract
More than 80% of colorectal cancer patients have adenomatous polyposis coli (APC) mutations, which induce abnormal WNT/β-catenin activation. Tankyrase (TNKS) mediates the release of active β-catenin, which occurs regardless of the ligand that translocates into the nucleus by AXIN degradation via the ubiquitin-proteasome pathway. Therefore, TNKS inhibition has emerged as an attractive strategy for cancer therapy. In this study, we identified pyridine derivatives by evaluating in vitro TNKS enzyme activity and investigated N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(2-cyanophenyl)piperidine-4-carboxamide (TI-12403) as a novel TNKS inhibitor. TI-12403 stabilized AXIN2, reduced active β-catenin, and downregulated β-catenin target genes in COLO320DM and DLD-1 cells. The antitumor activities of TI-12403 were confirmed by the viability of the colorectal cancer cells and its lack of visible toxicity in DLD-1 xenograft mouse model. In addition, combined 5-FU and TI-12403 treatment synergistically inhibited proliferation to a greater extent than that in a single drug treatment. Our observations suggest that TI-12403, a novel selective TNKS1 inhibitor, may be a suitable compound for anticancer drug development.
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30
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Zhao Y, Wang C, Goel A. Andrographis overcomes 5-fluorouracil-associated chemoresistance through inhibition of DKK1 in colorectal cancer. Carcinogenesis 2021; 42:814-825. [PMID: 33822896 PMCID: PMC8215595 DOI: 10.1093/carcin/bgab027] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/21/2021] [Accepted: 04/01/2021] [Indexed: 12/25/2022] Open
Abstract
Colorectal cancer (CRC) ranks as the third leading cause of cancer-related deaths in the USA. 5-Fluorouracil (5FU)-based chemotherapeutic drug remains a mainstay of CRC treatment. Unfortunately, ~50-60% of patients eventually develop resistance to 5FU, leading to poor survival outcomes. Our previous work revealed that andrographis enhanced 5FU-induced anti-cancer activity, but the underlying mechanistic understanding largely remains unclear. In this study, we first established 5FU-resistant (5FUR) CRC cells and observed that combined treatment with andrographis-5FU in 5FUR cells exhibited superior effect on cell viability, proliferation, and colony formation capacity compared with individual treatments (P < 0.001). To identify key genes and pathways responsible for 5FU resistance, we analyzed genome-wide transcriptomic profiling data from CRC patients who either responded or did not respond to 5FU. Among a panel of differentially expressed genes, Dickkopf-1 (DKK1) overexpression was a critical event for 5FU resistance. Moreover, andrographis significantly downregulated 5FU-induced DKK1 overexpression, accompanied with enhanced anti-tumor effects by abrogating downstream Akt-phosphorylation. In line with in vitro findings, andrographis enhanced 5FU-induced anti-cancer activity in mice xenografts and patient-derived tumoroids (P < 0.01). In conclusion, our data provide novel evidence for andrographis-mediated reversal of 5FU resistance, highlighting its potential role as an adjunct to conventional chemotherapy in CRC.
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Affiliation(s)
- Yinghui Zhao
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shandong Engineering and Technology Research Center for Tumor Marker Detection, Jinan, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan, China
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA
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31
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Wang Y, Wei Q, Chen Y, Long S, Yao Y, Fu K. Identification of Hub Genes Associated With Sensitivity of 5-Fluorouracil Based Chemotherapy for Colorectal Cancer by Integrated Bioinformatics Analysis. Front Oncol 2021; 11:604315. [PMID: 33912443 PMCID: PMC8071956 DOI: 10.3389/fonc.2021.604315] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 03/16/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors. 5-fluorouracil (5-FU) has been used for the standard first-line treatment for CRC patients for several decades. Although 5-FU based chemotherapy has increased overall survival (OS) of CRC patients, the resistance of CRC to 5-FU based chemotherapy is the principal cause for treatment failure. Thus, identifying novel biomarkers to predict response to 5-FU based chemotherapy is urgently needed. In the present study, the gene expression profile of GSE3964 from the Gene Expression Omnibus database was used to explore the potential genes related to intrinsic resistance to 5-FU. A gene module containing 81 genes was found to have the highest correlation with chemotherapy response using Weighted Gene Co-expression Network Analysis (WGCNA). Then a protein-protein interaction (PPI) network was constructed and ten hub genes (TGFBI, NID, LEPREL2, COL11A1, CYR61, PCOLCE, IGFBP7, COL4A2, CSPG2, and VTN) were identified using the CytoHubba plugin of Cytoscape. Seven of these hub genes showed significant differences in expression between chemotherapy-sensitive and chemotherapy-resistant samples. The prognostic value of these seven genes was evaluated using TCGA COAD (Colorectal Adenocarcinoma) data. The results showed that TGFBI was highly expressed in chemotherapy-sensitive patients, and patients with high TGFBI expression have better survival.
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Affiliation(s)
- Ya Wang
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Qunhui Wei
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China
| | - Yuqiao Chen
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Shichao Long
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yuanbing Yao
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Kai Fu
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.,Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.,Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China.,Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
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32
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Micallef I, Baron B. The Mechanistic Roles of ncRNAs in Promoting and Supporting Chemoresistance of Colorectal Cancer. Noncoding RNA 2021; 7:24. [PMID: 33807355 PMCID: PMC8103280 DOI: 10.3390/ncrna7020024] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/03/2021] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal Cancer (CRC) is one of the most common gastrointestinal malignancies which has quite a high mortality rate. Despite the advances made in CRC treatment, effective therapy is still quite challenging, particularly due to resistance arising throughout the treatment regimen. Several studies have been carried out to identify CRC chemoresistance mechanisms, with research showing different signalling pathways, certain ATP binding cassette (ABC) transporters and epithelial mesenchymal transition (EMT), among others to be responsible for the failure of CRC chemotherapies. In the last decade, it has become increasingly evident that certain non-coding RNA (ncRNA) families are involved in chemoresistance. Research investigations have demonstrated that dysregulation of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) contribute towards promoting resistance in CRC via different mechanisms. Considering the currently available data on this phenomenon, a better understanding of how these ncRNAs participate in chemoresistance can lead to suitable solutions to overcome this problem in CRC. This review will first focus on discussing the different mechanisms of CRC resistance identified so far. The focus will then shift onto the roles of miRNAs, lncRNAs and circRNAs in promoting 5-fluorouracil (5-FU), oxaliplatin (OXA), cisplatin and doxorubicin (DOX) resistance in CRC, specifically using ncRNAs which have been recently identified and validated under in vivo or in vitro conditions.
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Affiliation(s)
| | - Byron Baron
- Centre for Molecular Medicine and Biobanking, University of Malta, MSD2080 Msida, Malta;
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33
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Yang MD, Zhou WJ, Chen XL, Chen J, Ji Q, Li Q, Wang WH, Su SB. Therapeutic Effect and Mechanism of Bushen-Jianpi-Jiedu Decoction Combined with Chemotherapeutic Drugs on Postoperative Colorectal Cancer. Front Pharmacol 2021; 12:524663. [PMID: 33828479 PMCID: PMC8020259 DOI: 10.3389/fphar.2021.524663] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 01/14/2021] [Indexed: 11/16/2022] Open
Abstract
There is a lack of effective therapeutic drugs in patients with postoperative colorectal cancer (PCRC). This study aimed to investigate the therapeutic effect and mechanisms of Bushen-Jianpi-Jiedu decoction (BSJPJDD) combined with chemotherapeutic drugs (oxaliplatin) on PCRC with liver and kidney yin deficiency and spleen deficiency syndrome (LKYD-SDS) through the therapeutic evaluation of clinical therapy and the integrative analysis of network pharmacology, RNA-seq and label-free data, and experiment verification in vitro. In clinical therapy, the median progression-free survival (PFS) and Karnofsky performance score (KPS) were increased in PCRC patients by the aqueous extract of BSJPJDD combined with oxaliplatin treatment for three months, compared to oxaliplatin alone (p < 0.05). The integrative analysis showed that 559 differentially expressed genes (DEGs) and 11 differentially expressed proteins (DEPs) were regulated by BSJPJDD, among which seven bioactive compounds through 39 potential targets were involved in the regulation of multiple signaling pathways including MAPK, PI3K-Akt, and HIF-1, etc. In the experimental verification, an ELISA assay showed that plasma ZEB2, CAT, and KRT78 were decreased, and IL-1Α, CD5L, FBLN5, EGF, and KRT78 were increased in comparison to the above (p < 0.05). Furthermore, the SW620 cell viability was inhibited and the expressions of MAPK and the p-ERK/ERK ratio were significantly downregulated by the aqueous extract of BSJPJDD combined with oxaliplatin treatment, compared with oxaliplatin treatment alone (p < 0.05). These data suggested that BSJPJDD combined with oxaliplatin prolongs the survival and improves Karnofsky performance status of PCRC patients with LKYD-SDS, and may be associated with the regulation of multiple signaling pathways.
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Affiliation(s)
- Meng-Die Yang
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wen-Jun Zhou
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiao-Le Chen
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jian Chen
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Department of Vascular Disease, Shanghai TCM-Integrated Institute of Vascular Disease, Shanghai, China
| | - Qing Ji
- Department of Oncology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qi Li
- Department of Oncology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wen-Hai Wang
- Department of Oncology, Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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34
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Hasbal-Celikok G, Aksoy-Sagirli P, Altiparmak-Ulbegi G, Can A. Identification of AKT1/β-catenin mutations conferring cetuximab and chemotherapeutic drug resistance in colorectal cancer treatment. Oncol Lett 2021; 21:209. [PMID: 33574948 DOI: 10.3892/ol.2021.12470] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 11/19/2020] [Indexed: 12/24/2022] Open
Abstract
In anticancer therapy, the effectiveness of therapeutics is limited by mutations causing drug resistance. KRAS mutations are the only determinant for cetuximab resistance in patients with colorectal cancer (CRC). However, cetuximab treatment has not been fully successful in the majority of patients with wild-type (WT) KRAS. Therefore, it is important to determine new predictive mutations in CRC treatment. In the present study, the association between AKT1/β-catenin (CTNNB1) mutations with the drug resistance to cetuximab and other chemotherapeutics used in the CRC treatment was investigated by using site-directed mutagenesis, transfection, western blotting and cell proliferation inhibition assay. Cetuximab resistance was higher in the presence of AKT1 E17K, E49K and L52R mutations, as well as CTNNB1 T41A, S45F and S33P mutations compared with that of respective WT proteins. AKT1/CTNNB1 mutations were also associated with oxaliplatin, irinotecan, SN-38 and 5-fluorouracil resistance. Furthermore, mutant cell viability in oxaliplatin treatment was more effectively inhibited compared with that of the other chemotherapeutic drugs. In conclusion, AKT1/CTNNB1 mutations may be used as an important predictive biomarker in CRC treatment.
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Affiliation(s)
- Gozde Hasbal-Celikok
- Department of Biochemistry, Faculty of Pharmacy, Istanbul University, Fatih, Istanbul 34116, Turkey
| | - Pinar Aksoy-Sagirli
- Department of Biochemistry, Faculty of Pharmacy, Istanbul University, Fatih, Istanbul 34116, Turkey
| | - Gulsum Altiparmak-Ulbegi
- Department of Biochemistry, Faculty of Pharmacy, Istanbul University, Fatih, Istanbul 34116, Turkey
| | - Ayse Can
- Department of Biochemistry, Faculty of Pharmacy, Istanbul University, Fatih, Istanbul 34116, Turkey
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35
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Zhu YY, Jin Q, Chen SS, Jin DN, Wang ZJ, He YJ, Chen HC, Zhao YL, Zhao LX, Dai Z, Luo XD. Neothalfine, a potent natural anti-tumor agent against metastatic colorectal cancer and its primary mechanism. Bioorg Med Chem 2021; 29:115849. [PMID: 33221063 DOI: 10.1016/j.bmc.2020.115849] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 10/19/2020] [Accepted: 11/01/2020] [Indexed: 02/07/2023]
Abstract
Neothalfine is a natural bisbenzylisoquinoline alkaloid with the abundant resource in medicinal plants and has not been reported its anti-tumor efficacy. In the present study, the anti-tumor efficacy was investigated and it showed broad-spectrum activity against several cancer cell lines, especially metastatic colorectal cancer (HCT116, SW620, T84) with the IC50 values of 7.2, 5.9, 8.2 nM, respectively, roughly equal to well-known anti-tumor agent docetaxel (4.0, 4.7, 2.7 nM) and nearly 1000 folds than CPT-11 (4.4, 5.1, 6.9 μM). Furthermore, neothalfine inhibited colorectal cell proliferation by resulting in cell cycle arrest at the G2/M phase and induced apoptosis through the dysfunction of mitochondria to trigger intrinsic apoptotic pathway by untargeted metabolomic method, mitochondrial membrane potential, and caspase-3/7 activity assay. Moreover, neothalfine damaged colorectal cancer clonal spheres expansion significantly at the concentration of 3.5 nM with nearly 1000 folds efficacy than CPT-11 (3.0 µM). The results supported that neothalfine might be an anti-tumor lead for further investigation.
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Affiliation(s)
- Yan-Yan Zhu
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China
| | - Qiong Jin
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, People's Republic of China
| | - Shan-Shan Chen
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China
| | - Dan-Ni Jin
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China
| | - Zhao-Jie Wang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China
| | - Ying-Jie He
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China
| | - Hui-Cheng Chen
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China
| | - Yun-Li Zhao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China
| | - Li-Xing Zhao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China
| | - Zhi Dai
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China.
| | - Xiao-Dong Luo
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, People's Republic of China.
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36
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Ubels J, Schaefers T, Punt C, Guchelaar HJ, de Ridder J. RAINFOREST: a random forest approach to predict treatment benefit in data from (failed) clinical drug trials. Bioinformatics 2020; 36:i601-i609. [PMID: 33381829 DOI: 10.1093/bioinformatics/btaa799] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
MOTIVATION When phase III clinical drug trials fail their endpoint, enormous resources are wasted. Moreover, even if a clinical trial demonstrates a significant benefit, the observed effects are often small and may not outweigh the side effects of the drug. Therefore, there is a great clinical need for methods to identify genetic markers that can identify subgroups of patients which are likely to benefit from treatment as this may (i) rescue failed clinical trials and/or (ii) identify subgroups of patients which benefit more than the population as a whole. When single genetic biomarkers cannot be found, machine learning approaches that find multivariate signatures are required. For single nucleotide polymorphism (SNP) profiles, this is extremely challenging owing to the high dimensionality of the data. Here, we introduce RAINFOREST (tReAtment benefIt prediction using raNdom FOREST), which can predict treatment benefit from patient SNP profiles obtained in a clinical trial setting. RESULTS We demonstrate the performance of RAINFOREST on the CAIRO2 dataset, a phase III clinical trial which tested the addition of cetuximab treatment for metastatic colorectal cancer and concluded there was no benefit. However, we find that RAINFOREST is able to identify a subgroup comprising 27.7% of the patients that do benefit, with a hazard ratio of 0.69 (P = 0.04) in favor of cetuximab. The method is not specific to colorectal cancer and could aid in reanalysis of clinical trial data and provide a more personalized approach to cancer treatment, also when there is no clear link between a single variant and treatment benefit. AVAILABILITY AND IMPLEMENTATION The R code used to produce the results in this paper can be found at github.com/jubels/RAINFOREST. A more configurable, user-friendly Python implementation of RAINFOREST is also provided. Due to restrictions based on privacy regulations and informed consent of participants, phenotype and genotype data of the CAIRO2 trial cannot be made freely available in a public repository. Data from this study can be obtained upon request. Requests should be directed toward Prof. Dr. H.J. Guchelaar (h.j.guchelaar@lumc.nl). SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Joske Ubels
- Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.,Erasmus MC Cancer Institute, ErasmusMC, Rotterdam, The Netherlands.,SkylineDx, Rotterdam, The Netherlands.,Oncode Institute, Utrecht, The Netherlands
| | - Tilman Schaefers
- Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.,Oncode Institute, Utrecht, The Netherlands
| | - Cornelis Punt
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht,The Netherlands
| | - Henk-Jan Guchelaar
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jeroen de Ridder
- Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.,Oncode Institute, Utrecht, The Netherlands
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37
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Varughese LA, Lau-Min KS, Cambareri C, Damjanov N, Massa R, Reddy N, Oyer R, Teitelbaum U, Tuteja S. DPYD and UGT1A1 Pharmacogenetic Testing in Patients with Gastrointestinal Malignancies: An Overview of the Evidence and Considerations for Clinical Implementation. Pharmacotherapy 2020; 40:1108-1129. [PMID: 32985005 PMCID: PMC8796462 DOI: 10.1002/phar.2463] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Gastrointestinal (GI) malignancies are among the most commonly diagnosed cancers worldwide. Despite the introduction of targeted and immunotherapy agents in the treatment landscape, cytotoxic agents, such as fluoropyrimidines and irinotecan, remain as the cornerstone of chemotherapy for many of these tumors. Pharmacogenetics (PGx) is a rapidly evolving field that accounts for interpatient variability in drug metabolism to predict therapeutic response and toxicity. Given the significant incidence of severe treatment-related adverse events associated with cytotoxic agents, utilizing PGx can allow clinicians to better anticipate drug tolerability while minimizing treatment interruptions or delays. In this review, the PGx profiles of drug-gene pairs with potential impact in GI malignancy therapy - DPYD-5-fluorouracil/capecitabine and UGT1A1-irinotecan - and the available clinical evidence of their roles in reducing severe adverse events are discussed. Considerations for clinical implementation, such as optimal laboratory workflows, electronic health record integration, and stakeholder engagement, as well as provider education, are addressed. Last, exploratory PGx markers in GI malignancy treatment are described. As the PGx knowledge base rapidly evolves, pharmacists will be vital in leveraging their pharmacology knowledge and clinical skills to implement PGx testing in the clinic.
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Affiliation(s)
- Lisa A. Varughese
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kelsey S. Lau-Min
- Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Christine Cambareri
- Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Nevena Damjanov
- Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ryan Massa
- Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Nandi Reddy
- Ann B. Barshinger Cancer Institute, Penn Medicine at Lancaster General Health, Lancaster, Pennsylvania
| | - Randall Oyer
- Ann B. Barshinger Cancer Institute, Penn Medicine at Lancaster General Health, Lancaster, Pennsylvania
| | - Ursina Teitelbaum
- Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sony Tuteja
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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38
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Sabeti Aghabozorgi A, Moradi Sarabi M, Jafarzadeh-Esfehani R, Koochakkhani S, Hassanzadeh M, Kavousipour S, Eftekhar E. Molecular determinants of response to 5-fluorouracil-based chemotherapy in colorectal cancer: The undisputable role of micro-ribonucleic acids. World J Gastrointest Oncol 2020; 12:942-956. [PMID: 33005290 PMCID: PMC7510001 DOI: 10.4251/wjgo.v12.i9.942] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 05/11/2020] [Accepted: 07/19/2020] [Indexed: 02/05/2023] Open
Abstract
5-flurouracil (5-FU)-based chemotherapy is the main pharmacological therapy for advanced colorectal cancer (CRC). Despite significant progress in the treatment of CRC during the last decades, 5-FU drug resistance remains the most important cause of failure in CRC therapy. Resistance to 5-FU is a complex and multistep process. Different mechanisms including microsatellite instability, increased expression level of key enzyme thymidylate synthase and its polymorphism, increased level of 5-FU-activating enzymes and mutation of TP53 are proposed as the main determinants of resistance to 5-FU in CRC cells. Recently, micro-ribonucleic acids (miRNA) and their alterations were found to have a crucial role in 5-FU resistance. In this regard, the miRNA-mediated mechanisms of 5-FU drug resistance reside among the new fields of pharmacogenetics of CRC drug response that has not been completely discovered. Identification of the biological markers that are related to response to 5-FU-based chemotherapy is an emerging field of precision medicine. This approach will have an important role in defining those patients who are most likely to benefit from 5-FU-based chemotherapy in the future. Thereby, the identification of 5-FU drug resistance mechanisms is an essential step to predict and eventually overcome resistance. In the present comprehensive review, we will summarize the latest knowledge regarding the molecular determinants of response to 5-FU-based chemotherapy in CRC by emphasizing the role of miRNAs.
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Affiliation(s)
| | - Mostafa Moradi Sarabi
- Department of Biochemistry and Genetics, School of Medicine, Lorestan University of Medical Sciences, Khorramabad 381251698, Iran
| | - Reza Jafarzadeh-Esfehani
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 1394491388, Iran
| | - Shabnaz Koochakkhani
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
| | - Marziyeh Hassanzadeh
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
| | - Soudabeh Kavousipour
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
| | - Ebrahim Eftekhar
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
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39
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Gagno S, Bartoletti M, Romualdi C, Poletto E, Scalone S, Sorio R, Zanchetta M, De Mattia E, Roncato R, Cecchin E, Giorda G, Toffoli G. Pharmacogenetic score predicts overall survival, progression-free survival and platinum sensitivity in ovarian cancer. Pharmacogenomics 2020; 21:995-1010. [PMID: 32894980 DOI: 10.2217/pgs-2020-0049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To define the impact of polymorphisms in genes involved in platinum-taxane and estrogen activity in the outcome of platinum-based treated ovarian cancer patients (OCP). Patients & Methods: Two hundred and thirty OCP were analyzed for 124 germ-line polymorphisms to generate a prognostic score for overall survival (OS), progression-free survival (PFS) and platinum-free interval (PFI). Results: ABCG2 rs3219191D>I, UGT1A rs10929302G>A and UGT1A rs2741045T>C polymorphisms were significantly associated with all three parameters (OS, PFS and PFI) and were used to generate a score. Patients in high-risk group had a poorer OS (hazard ratio [HR]: 1.8; 95% CI: 1.3-2.7; p = 0.0019), PFS (HR: 2.0; 95% CI: 1.4-2.9; p < 0.0001) and PFI (HR: 1.9; 95% CI: 1.4-2.8; p = 0.0002) compared with those in low-risk group. Conclusion: The prognostic-score including polymorphisms involved in drug and estrogen pathways stratifies OCP according to OS, PFS and PFI.
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Affiliation(s)
- Sara Gagno
- Experimental & Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Michele Bartoletti
- Department of Medicine (DAME), University of Udine, Via Palladio 8, 33100, Udine, Italy.,Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Chiara Romualdi
- Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35122, Padova, Italy
| | - Elena Poletto
- Department of Oncology, ASUI Udine University Hospital, Via Pozzuolo 330, 33100, Udine, Italy
| | - Simona Scalone
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Roberto Sorio
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Martina Zanchetta
- Experimental & Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Elena De Mattia
- Experimental & Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Rossana Roncato
- Experimental & Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Erika Cecchin
- Experimental & Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Giorgio Giorda
- Gynaecological Oncology Unit, Centro di Riferimento Oncologico (CRO) di Aviano, IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Giuseppe Toffoli
- Experimental & Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
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40
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Wu R, Yow C, Law E, Chu E, Huang Z. Effect of Foslip® mediated photodynamic therapy on 5-fluorouracil resistant human colorectal cancer cells. Photodiagnosis Photodyn Ther 2020; 31:101945. [PMID: 32768589 DOI: 10.1016/j.pdpdt.2020.101945] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/27/2020] [Accepted: 07/31/2020] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the commonest cancer in Hong Kong and is often treated with 5-fluorouracil (5-FU). However the clinical application of 5-FU was limited by drug resistance in CRC. Photodynamic therapy (PDT) is a novel treatment combating CRC via the combination of photosensitizer, molecular oxygen and light activation. In this study, 5-FU resistant HT29 (HT29FU) was established and its susceptibility to Foslip® PDT tested. Effect of 5-FU to HT29 cells was measured via qPCR. Efficacy of Foslip® PDT on HT29 and HT29FU cells were measured via photosensitizer uptake, cellular localization, cytotoxicity, cell cycle distribution and signal proteins expression. 5-FU significantly induced ABCB1 mRNA expression in HT29 cells; whereas with a 24 fold increase in HT29FU cells. Both cells responded similarly to Foslip® PDT, with the inhibitory concentration IC20, IC50 and IC70 achieved at 1 ng/mL, 2 ng/mL and 5 ng/mL with 2 J/cm2 light activation respectively. Foslip® PDT triggered apoptosis and reduced JNK protein expression at IC70 on both cells. Effect of Foslip® PDT on HT29 cells was independent to 5-FU resistance properties. Therefore, Foslip® PDT could be a potential treatment for 5-FU resistant cancer patients. Further investigations on the Foslip® PDT mediated molecular changes in HT29FU cells deserve to be explored.
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Affiliation(s)
- Rwk Wu
- School of Medical and Health Sciences, Tung Wah College, HKSAR, Hong Kong, China.
| | - Cmn Yow
- Medical Laboratory Science, Department of Health Technology & Informatics, Hong Kong Polytechnic University, HKSAR, Hong Kong, China
| | - Eric Law
- Medical Laboratory Science, Department of Health Technology & Informatics, Hong Kong Polytechnic University, HKSAR, Hong Kong, China
| | - Esm Chu
- School of Medical and Health Sciences, Tung Wah College, HKSAR, Hong Kong, China
| | - Zheng Huang
- MOE Key Laboratory of Photonics Science and Technology for Medicine, Fujian Normal University, Fuzhou, China.
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41
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Duran G, Cruz R, Simoes AR, Barros F, Giráldez JM, Bernárdez B, Anido U, Candamio S, López-López R, Carracedo Á, Lamas MJ. Efficacy and toxicity of adjuvant chemotherapy on colorectal cancer patients: how much influence from the genetics? J Chemother 2020; 32:310-322. [PMID: 32441565 DOI: 10.1080/1120009x.2020.1764281] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We studied the predictive value for response and toxicity of functional polymorphisms in genes involved in the oxaliplatin/fluorouracil pathway in colorectal cancer patients. One hundred and twenty-seven (127) patients were treated with curative intended surgery followed by adjuvant chemotherapy with FOLFOX (fluorouracil, leucovorin and oxaliplatin) regimen. The median age was 65.53 (27-80) years (66.9% male, 59.1% rectum). The median follow-up was 8.5 years (IQR, 4.1-9.4). At the end of follow-up, 59 patients (46.5%) had relapsed or died in the whole study population. We did find that XRCC1GG genotype is associated with a higher risk of developing haematologic toxicity. Furthermore, we report a significant association of the TS 3'UTR 6 bp/6 bp polymorphism and the XRCC1 rs25487 with a higher risk of developing anaemia and diarrhoea, respectively. On the other hand, none of the studied polymorphisms showed clinically relevant association with disease-free survival and overall survival or early failure to adjuvant FOLFOX therapy.
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Affiliation(s)
- Goretti Duran
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.,Pharmacy Department, University Hospital of Santiago (SERGAS), Santiago de Compostela, Spain
| | - Raquel Cruz
- Center for Biomedical Research on Rare Diseases (CIBERER), Genomics Medicine Group, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ana Rita Simoes
- Fundación Instituto de Investigación Sanitaria de Santiago (FIDIS), Santiago de Compostela, Spain.,Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía, Obstetricia e Pediatría, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain.,Genomics Medicine Group, Galician Public Foundation of Genomic Medicine (FPGMX), Santiago de Compostela, Spain
| | - Francisco Barros
- Genomics Medicine Group, Galician Public Foundation of Genomic Medicine (FPGMX), Santiago de Compostela, Spain
| | - José María Giráldez
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.,Pharmacy Department, University Hospital of Santiago (SERGAS), Santiago de Compostela, Spain
| | - Beatriz Bernárdez
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.,Pharmacy Department, University Hospital of Santiago (SERGAS), Santiago de Compostela, Spain
| | - Urbano Anido
- Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain.,Medical Oncology Department, University Hospital of Santiago (SERGAS), Santiago de Compostela, Spain
| | - Sonia Candamio
- Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain.,Medical Oncology Department, University Hospital of Santiago (SERGAS), Santiago de Compostela, Spain
| | - Rafael López-López
- Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain.,Medical Oncology Department, University Hospital of Santiago (SERGAS), Santiago de Compostela, Spain.,Liquid Biopsy Analysis Unit, Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain
| | - Ángel Carracedo
- Genomics Medicine Group, CIBERER, Galician Public Foundation of Genomic Medicine (FPGMX), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - María Jesús Lamas
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.,Pharmacy Department, University Hospital of Santiago (SERGAS), Santiago de Compostela, Spain
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42
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Wang XX, Yu PC, Li J. High-Throughput Metabolomics for Identification of Metabolic Pathways and Deciphering the Effect Mechanism of Dioscin on Rectal Cancer From Cell Metabolic Profiles Coupled With Chemometrics Analysis. Front Pharmacol 2020; 11:68. [PMID: 32180713 PMCID: PMC7059176 DOI: 10.3389/fphar.2020.00068] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 01/24/2020] [Indexed: 01/05/2023] Open
Abstract
High-throughput liquid chromatography-mass spectrometry (LC-MS)-based metabolomics can provide the holistic analysis of the low molecular weight endogenous metabolites in cells and reflect the changes of cellular regulation and metabolic pathways. Our study designed to reveal the potentially pharmacological effects of dioscin on SW480 rectal cancer cells using nontargeted metabolomics method to probe into small molecular metabolites and pathway changes. After the cell assay of proliferation, apoptosis, migration, and invasion, the dioscin-treated cell samples were prepared for nontargeted metabolomics analysis based on LC-MS tool to describe the metabolic profiles. Dioscin has prevented cell proliferation and accelerated cell apoptosis, and it also inhibited the SW480 rectal cancer cells' migration and invasion. A total of 22 metabolites were selected as promising biomarkers of pharmacological reaction of dioscin to rectal cancer, and eight highly correlated pathways including D-glutamine and D-glutamate metabolism, pyruvate metabolism, arachidonic acid metabolism, phenylalanine metabolism, tryptophan metabolism, glycolysis or gluconeogenesis, citrate cycle (TCA cycle), and butanoate metabolism were identified. It showed that strategies based on cell metabolomics are helpful tools to discover the small molecular metabolites to elucidate the action mechanism of drug.
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Affiliation(s)
- Xin-Xin Wang
- Heilongjiang Province Land Reclamation Headquarters General Hospital, Heilongjiang Agriculture and Reclamation Bureau, Harbin, China
| | - Peng-cheng Yu
- College of Traditional Chinese Medicine, Jilin Agricultural University, Changchun, China
| | - Jun Li
- Department of Orthopedics, The Affiliated First Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
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43
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Tieng FYF, Baharudin R, Abu N, Mohd Yunos RI, Lee LH, Ab Mutalib NS. Single Cell Transcriptome in Colorectal Cancer-Current Updates on Its Application in Metastasis, Chemoresistance and the Roles of Circulating Tumor Cells. Front Pharmacol 2020; 11:135. [PMID: 32174835 PMCID: PMC7056698 DOI: 10.3389/fphar.2020.00135] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 01/31/2020] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is among the most common cancer worldwide, a challenge for research, and a model for studying the molecular mechanisms involved in its development. Previously, bulk transcriptomics analyses were utilized to classify CRC based on its distinct molecular and clinicopathological features for prognosis and diagnosis of patients. The introduction of single-cell transcriptomics completely turned the table by enabling the examination of the expression levels of individual cancer cell within a single tumor. In this review, we highlighted the importance of these single-cell transcriptomics analyses as well as suggesting circulating tumor cells (CTCs) as the main focus of single-cell RNA sequencing. Characterization of these cells might reveal the intratumoral heterogeneity present in CRC while providing critical insights into cancer metastasis. To summarize, we believed the analysis of gene expression patterns of CTC from CRC at single-cell resolution holds the potential to provide key information for identification of prognostic and diagnostic markers as well as the development of precise and personalized cancer treatment.
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Affiliation(s)
- Francis Yew Fu Tieng
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Rashidah Baharudin
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nadiah Abu
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Ryia-Illani Mohd Yunos
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Learn-Han Lee
- Novel Bacteria and Drug Discovery Research Group, Microbiome and Bioresource Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Subang Jaya, Malaysia
| | - Nurul-Syakima Ab Mutalib
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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44
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Zhang G, Luo X, Zhang W, Chen E, Xu J, Wang F, Cao G, Ju Z, Jin D, Huang X, Zhou W, Song Z. CXCL-13 Regulates Resistance to 5-Fluorouracil in Colorectal Cancer. Cancer Res Treat 2020; 52:622-633. [PMID: 32019285 PMCID: PMC7176956 DOI: 10.4143/crt.2019.593] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 12/29/2019] [Indexed: 12/24/2022] Open
Abstract
Purpose 5-Fluorouracil (5-Fu) is used as a conventional chemotherapy drug in chemotherapy for patients with advanced colorectal cancer, but many patients still suffer from treatment failure due to 5-Fu resistance. Emerging observations revealed the important role of chemokine (C-X-C motif) ligand 13 (CXCL-13) in tumor microenvironment and its relationship with prognosis in patients with colorectal cancer. This study is designed to reveal the important role of CXCL-13 in causing colorectal cancer resistance to 5-Fu. Materials and Methods CXCL-13 levels of patient's serum or cell culture supernatants were measured separately by enzyme-linked immunosorbent assay. In cell assays, cell viability is detected by Cell Counting Kit-8. Therefore, the recombinant human CXCL-13 was used to simulate its high expression in cells while its antibody and siRNA were used to reduce CXCL-13 expression in cells. Results In this study, we demonstrated that CXCL-13 is associated with 5-Fu resistance by culture medium exchange experiments and cytokine arrays of colorectal cancer resistant and non-resistant cells. Clinical studies showed that CXCL-13 is highly expressed in the serum of 5-Fu–resistant patients. High levels of serum CXCL-13 also predict a worse clinical outcome. The addition of recombinant CXCL-13 cytokine resulted in 5-Fu resistance, while its antibody overcame 5-Fu resistance, and knockdown of CXCL-13 expression by siRNA also reduced 5-Fu resistance, which can be saved by added recombination CXCL-13. Conclusion These results not only identify a CXCL-13 mediated 5-Fu resistance mechanism but also provide a novel target for 5-Fu–resistant colorectal cancer in prevention and treatment strategies.
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Affiliation(s)
- Guolin Zhang
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, China.,Zhejiang Province Key Laboratory of Biological Treatment, Hangzhou, China
| | - Xin Luo
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, China.,Zhejiang Province Key Laboratory of Biological Treatment, Hangzhou, China
| | - Wei Zhang
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, China.,Zhejiang Province Key Laboratory of Biological Treatment, Hangzhou, China
| | - Engeng Chen
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, China.,Zhejiang Province Key Laboratory of Biological Treatment, Hangzhou, China
| | - Jianbin Xu
- Zhejiang Province Key Laboratory of Biological Treatment, Hangzhou, China
| | - Fei Wang
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, China
| | - Gaoyang Cao
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, China
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China
| | - Dongai Jin
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, China
| | - Xuefeng Huang
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, China.,Zhejiang Province Key Laboratory of Biological Treatment, Hangzhou, China
| | - Wei Zhou
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, China
| | - Zhangfa Song
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, China.,Zhejiang Province Key Laboratory of Biological Treatment, Hangzhou, China
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45
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Cantor DI, Cheruku HR, Westacott J, Shin JS, Mohamedali A, Ahn SB. Proteomic investigations into resistance in colorectal cancer. Expert Rev Proteomics 2020; 17:49-65. [PMID: 31914823 DOI: 10.1080/14789450.2020.1713103] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Despite advances in screening and treatment options, colorectal cancer (CRC) remains one of the most prevalent and lethal cancer subtypes. Resistance to cytotoxic or targeted therapy has remained a constant challenge to the treatment and long-term management of patients, attracting intense worldwide investigation since the 1950s. Through extensive investigations into the proteomic mechanisms and functions that convey resistance to therapy/s, researchers have become able to implicate alterations in several signaling pathways that provide and sustain resistance to treatment.Areas covered: In this review, we summarize how protein alterations are associated with resistance to therapy, with particular emphasis on CRC. An overview of the mechanisms of therapeutic resistance is described, highlighting recent studies which endeavor to elucidate the proteomic changes that are associated with the acquisition and promulgation of therapeutic resistance.Expert opinion: While cancers such as CRC have been intensively studied for decades, unresponsiveness and the resistance to therapy remain critical obstacles in the treatment of patients. Due to the inherent biological and clinical heterogeneity of individual CRCs, proteomic methods stand to become powerful tools to provide biological insights that may guide therapeutic strategies with the ultimate goal of refining emergent immunotherapeutic treatments.
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Affiliation(s)
- David I Cantor
- Australian Proteome Analysis Facility, Macquarie University, Sydney, Australia
| | | | - Jack Westacott
- Faculty of Science and Engineering, Macquarie University, Sydney, Australia
| | - Joo-Shik Shin
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and Faculty of Medicine, University of Sydney, Sydney, Australia
| | - Abidali Mohamedali
- Faculty of Science and Engineering, Macquarie University, Sydney, Australia
| | - Seong Boem Ahn
- Faculty of Health and Medical Sciences, Macquarie University, Sydney, Australia
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Vaseghi Maghvan P, Jeibouei S, Akbari ME, Niazi V, Karami F, Rezvani A, Ansarinejad N, Abbasinia M, Sarvari G, Zali H, Talaie R. Personalized medicine in colorectal cancer. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2020; 13:S18-S28. [PMID: 33585000 PMCID: PMC7881405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Colorectal cancer (CRC) is a heterogeneous disease with various genetic and epigenetic factors leading to difficulties in response to both the therapy and drug resistance. Moreover, even in tumors with similar histopathological characteristics, different responses and molecular features could be observed because of the genetic basis and its interactions with the living environment. Through personalized medicine, we can classify patients into separate groups according to their genetic and epigenetic features and their susceptibility for a specific disease which could help with choosing the best therapeutic approach. In this review, genetic and epigenetic factors that cause heterogeneity in colorectal cancer are evaluated and proper drug administration in both chemotherapy and target therapy are suggested.
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Affiliation(s)
- Padina Vaseghi Maghvan
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Jeibouei
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Vahid Niazi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farshid Karami
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Rezvani
- Department of Hematology, Medical Oncology and Stem Cell Transplantation, Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nafiseh Ansarinejad
- Department of Hematology and Oncology, Iran University of medical science, Tehran, Iran
| | | | - Gisoo Sarvari
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran – Iran
| | - Hakimeh Zali
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ramin Talaie
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Vodenkova S, Buchler T, Cervena K, Veskrnova V, Vodicka P, Vymetalkova V. 5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future. Pharmacol Ther 2019; 206:107447. [PMID: 31756363 DOI: 10.1016/j.pharmthera.2019.107447] [Citation(s) in RCA: 580] [Impact Index Per Article: 96.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 11/13/2019] [Indexed: 02/07/2023]
Abstract
5-Fluorouracil (5-FU) is an essential component of systemic chemotherapy for colorectal cancer (CRC) in the palliative and adjuvant settings. Over the past four decades, several modulation strategies including the implementation of 5-FU-based combination regimens and 5-FU pro-drugs have been developed and tested to increase the anti-tumor activity of 5-FU and to overcome the clinical resistance. Despite the encouraging progress in CRC therapy to date, the patients' response rates to therapy continue to remain low and the patients' benefit from 5-FU-based therapy is frequently compromised by the development of chemoresistance. Inter-individual differences in the treatment response in CRC patients may originate in the unique genetic and epigenetic make-up of each individual. The critical element in the current trend of personalized medicine is the proper comprehension of causes and mechanisms contributing to the low or lack of sensitivity of tumor tissue to 5-FU-based therapy. The identification and validation of predictive biomarkers for existing 5-FU-based and new targeted therapies for CRC treatment will likely improve patients' outcomes in the future. Herein we present a comprehensive review summarizing options of CRC treatment and the mechanisms of 5-FU action at the molecular level, including both anabolic and catabolic ways. The main part of this review comprises the currently known molecular mechanisms underlying the chemoresistance in CRC patients. We also focus on various 5-FU pro-drugs developed to increase the amount of circulating 5-FU and to limit toxicity. Finally, we propose future directions of personalized CRC therapy according to the latest published evidence.
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Affiliation(s)
- Sona Vodenkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic; Department of Medical Genetics, Third Faculty of Medicine, Charles University, Ruska 2411/87, 100 00 Prague, Czech Republic
| | - Tomas Buchler
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Videnska 800, 140 59 Prague, Czech Republic
| | - Klara Cervena
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
| | - Veronika Veskrnova
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Videnska 800, 140 59 Prague, Czech Republic
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 323 00 Pilsen, Czech Republic.
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Liu A, Qiao J, He L, Liu Z, Chen J, Pei F, Du Y. Nitrogen Permease Regulator-Like-2 Exhibited Anti-Tumor Effects And Enhanced The Sensitivity Of Colorectal Cancer Cells To Oxaliplatin And 5-Fluorouracil. Onco Targets Ther 2019; 12:8637-8644. [PMID: 31695423 PMCID: PMC6805118 DOI: 10.2147/ott.s219562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 09/10/2019] [Indexed: 11/23/2022] Open
Abstract
Background Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Our previous study revealed that nitrogen permease regulator-like-2 (NPRL2), a promising anti-tumor gene, was downregulated at both the blood and tissue levels in CRC patients compared with that in healthy individuals. Purpose This study aims to explore the role of NPRL2 in CRC. Methods Herein, we constructed NPRL2 overexpression lentivirus vectors and transfected them into HT29 cells. The transfected cells were inoculated subcutaneously into nude mice. Tumor growth, pathology, apoptosis, and the protein expression of caspase-3, caspase-7, Bax, Bcl-2, and phosphorylated protein kinase B (p-Akt) were evaluated. To further explore whether NPRL2 could reduce drug resistance of CRC cells against oxaliplatin (L-OHP) and 5-fluorouracil (5-FU), we constructed a tumor model using HT29 cells. The tumor model was treated with lentiviral particles assembled with vectors encoding NPRL2 and exposed to L-OHP and 5-FU. Tumor growth, pathology, apoptosis, and the protein expression of caspase-3, caspase-7, Bax, Bcl-2, p-Akt, P-glycoprotein (P-gp), and multidrug resistance protein 1 (MRP1) were evaluated. Results The results indicated that in the in vivo CRC xenograft model, NPRL2 reduced the tumor volume and weight and enhanced apoptosis. Our results also confirmed that NPRL2 enhanced the sensitivity of CRC cells to L-OHP and 5-FU. Our studies further demonstrated that NPRL2 exerted anti-tumor and anti-drug resistance effects through the caspase-3, caspase-7, Bax, Bcl-2, Akt, P-gp, and MRP1 pathways. Conclusion Our present work demonstrated that NPRL2 exhibited anti-tumor effects and enhanced the sensitivities of CRC cells to L-OHP and 5-FU through the P-gp and MRP1 pathways.
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Affiliation(s)
- Aiyun Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Jiutao Qiao
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Liyuan He
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Zhangmeng Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Jing Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Fenghua Pei
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Yaju Du
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
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Sinner HF, Johnson J, Rychahou PG, Watt DS, Zaytseva YY, Liu C, Evers BM. Novel chemotherapeutic agent, FND-4b, activates AMPK and inhibits colorectal cancer cell proliferation. PLoS One 2019; 14:e0224253. [PMID: 31648230 PMCID: PMC6812860 DOI: 10.1371/journal.pone.0224253] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 10/10/2019] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer deaths in the US with the majority of deaths due to metastatic disease. Current chemotherapeutic regimens involve highly toxic agents, which limits their utility; therefore, more effective and less toxic agents are required to see a reduction in CRC mortality. Novel fluorinated N,N’-diarylureas (FND) were developed and characterized by our group as potent activators of adenosine monophosphate-activated kinase (AMPK) that inhibit cell cycle progression. The purpose of this study was to determine the effect of a lead FND compound, FND-4b, either alone or combined with PI-103 (a dual PI3K/mTOR inhibitor) or SN-38 (active metabolite of irinotecan) on cell cycle arrest and apoptosis of CRC cell lines (both commercially-available and novel lines established from our patient population). Treatment with FND-4b for 24h resulted in a marked induction of phosphorylated AMPK expression and a concomitant reduction in markers of cell proliferation, such as cyclin D1, in all CRC cell lines. Apoptosis was also notably increased in CRC cells treated with FND-4b. Regardless of the genetic profile of the CRC cells, FND-4b treatment alone resulted in decreased cell proliferation. Moreover, the combination of FND-4b with PI-103 resulted in increased cell death in all cell lines, while the combination of FND-4b with SN-38 resulted in increased cell death in select cell lines. Our findings identify FND-4b, which activates AMPK at micromolar concentrations, as a novel and effective inhibitor of CRC growth either alone or in combination with PI-103 and SN-38.
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Affiliation(s)
- Heather F. Sinner
- Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America
| | - Jeremy Johnson
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, United States of America
| | - Piotr G. Rychahou
- Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America
| | - David S. Watt
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
- Center for Molecular Medicine, Organic Synthesis Core, University of Kentucky, Lexington, Kentucky, United States of America
| | - Yekaterina Y. Zaytseva
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, United States of America
| | - Chunming Liu
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
| | - B. Mark Evers
- Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America
- * E-mail:
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Yao W, Lin Z, Shi P, Chen B, Wang G, Huang J, Sui Y, Liu Q, Li S, Lin X, Liu Q, Yao H. Delicaflavone induces ROS-mediated apoptosis and inhibits PI3K/AKT/mTOR and Ras/MEK/Erk signaling pathways in colorectal cancer cells. Biochem Pharmacol 2019; 171:113680. [PMID: 31669234 DOI: 10.1016/j.bcp.2019.113680] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 10/13/2019] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors worldwide and tends to have drug resistance. Delicaflavone (DLF), a novel anticancer agent of biflavonoid from Selaginella doederleinii Hieron, showed strong anti-CRC activities, which has not yet been reported. In this study, we investigated the effects and possible anti-CRC mechanism of DLF in vitro and in vivo. It was shown that DLF significantly inhibited the cells viability and induced G2/M phase arrest, apoptosis, the loss of mitochondrial membrane potential (Δψm), generation of ROS and increase of intracellular Ca2+ in HT29 and HCT116 cells by MTT assay, TEM, flow cytometry and inverted fluorescence microscope. Western blot and qPCR assays results further confirmed DLF induced caspase-dependent apoptosis and inhibited PI3K/AKT/mTOR and Ras/MEK/Erk signaling pathways in CRC cells. Meanwhile, DLF significantly suppressed the tumor growth via activation of Caspase-9 and Caspase-3 protein and decrease of ki67 and CD34 protein without apparent side effects in vivo. In summary, these results indicated DLF induced ROS-mediated cell cycle arrest and apoptosis through ER stress and mitochondrial pathway accompanying with the inhibition of PI3K/AKT/mTOR and Ras/MEK/Erk signaling cascade. Thus DLF could be a potential therapeutic agent for CRC.
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Affiliation(s)
- Wensong Yao
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China; College of Medical Sciences, Ningde Normal University, Ningde 352100, China
| | - Zhen Lin
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China
| | - Peiying Shi
- Department of Traditional Chinese Medicine Resource and Bee Products, Bee Science College, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Bing Chen
- Nano Medical Technology Research Institute, Fujian Medical University, Fuzhou 350122, China
| | - Gang Wang
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China
| | - Jianyong Huang
- Department of Pharmaceutics, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Yuxia Sui
- Department of Pharmacy, Provincial Clinical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China
| | - Qicai Liu
- Department of Reproductive Medicine Centre, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Shaoguang Li
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China.
| | - Xinhua Lin
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China; Nano Medical Technology Research Institute, Fujian Medical University, Fuzhou 350122, China; Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, Fujian Medical University, Fuzhou 350122, China.
| | - Qicai Liu
- Nano Medical Technology Research Institute, Fujian Medical University, Fuzhou 350122, China
| | - Hong Yao
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China; Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, Fujian Medical University, Fuzhou 350122, China.
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