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Liu C, Liu J, Shao J, Zhao X, Xie L, Shang M, Li Y, Li W. Single-cell and bulk transcriptome sequencing identifies circadian rhythm disruption and cluster-specific clinical insights in colorectal tumorigenesis. Discov Oncol 2025; 16:693. [PMID: 40338428 PMCID: PMC12062483 DOI: 10.1007/s12672-025-02521-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Accepted: 04/28/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common malignant tumors in the digestive system worldwide, with its mortality ranking second among all cancers. Studies have indicated that disruptions in circadian rhythm (CR) are associated with the occurrence of various cancers; however, the relationship between CR and CRC requires further evidence, and research on the application of CR in CRC is still limited. METHODS In this study, we employed both bulk and single-cell RNA sequencing to explore the dysregulation of CR in patients with CRC. By constructing a CR subtype classifier, we conducted an in-depth analysis of the prognostic significance, the status of the tumor microenvironment, and response to immune checkpoint blockade (ICB) therapy between different CR clusters. Furthermore, we developed a CR scoring system (CRS) using machine learning to predict overall survival and identified several genes as potential targets affecting CRC prognosis. RESULTS Our findings revealed significant alterations in CR genes and status between CRC and normal tissues using bulk and single-cell transcriptome sequencing. Patients with CRC could be categorized into two distinct CR clusters (CR cluster 1 and 2). The prognosis of CR cluster 2, with higher epithelial-mesenchymal transition (EMT) and angiogenesis scores, was significantly worser than that of CR cluster 1. These clusters exhibited distinct levels of tumor-infiltrating lymphocytes. CR cluster 2 with a notably higher proportion of patients with microsatellite-instability-high (MSI-H), potentially benefit from ICB therapy. The proportion of patients belonging to consensus molecular subtype 4 (CMS4) in CR cluster 2 was also notably higher than in CR cluster 1. Additionally, the CRS combined with tumor stage demonstrated superior overall survival prediction efficacy compared to traditional tumor stage. We revealed a potential link between model genes (LSAMP, MS4A2, NAV3, RAB3B, SIX4) and the disruption of CR and patient prognosis. CONCLUSION This study not only provide new insights into the assessment of CR status in CRC patients but also develop a prognosis model based on CR-related genes, offering a new tool for personalized risk assessment in CRC.
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Affiliation(s)
- Chen Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang Province, China
| | - Jingyang Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang Province, China
| | - Jing Shao
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang Province, China
| | - Xiaoman Zhao
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang Province, China
| | - Lin Xie
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang Province, China
| | - Mengyao Shang
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang Province, China
| | - Ying Li
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang Province, China
| | - Weiming Li
- Department of Orthopaedics, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China.
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2
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Cao L, Dai H, Wei S, Ba Y, Chen F, Chen Y, Yu C, Zhang S, Chen E, Zhang H. Endoplasmic reticulum stress-related prognosis signature characterizes the immune landscape and predicts the prognosis of colon adenocarcinoma. Front Genet 2025; 16:1516232. [PMID: 40236629 PMCID: PMC11996786 DOI: 10.3389/fgene.2025.1516232] [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: 10/24/2024] [Accepted: 03/17/2025] [Indexed: 04/17/2025] Open
Abstract
Background Colon adenocarcinoma (COAD) is characterized by high mortality and poor prognosis. Endoplasmic reticulum stress-related gene (ERSG) plays an indispensable role in the progression and immunotherapy of COAD. In this study, we evaluated the prognostic value of ERSGs in COAD. Methods We constructed and validated the ERSG-related prognostic signature based on public databases using univariate Cox analysis, Kaplan-Meier survival analysis, the LASSO method, and multivariate Cox analysis. In addition, TCGA-COAD, the Human Protein Atlas, and quantitative real-time PCR (q-PCR) were used to detect the mRNA and protein expressions of ERSGs in normal and cancer tissues/cells. The immunotherapeutic cohort was used to evaluate the predictive value of the ERSG signature for immunotherapeutic sensitivity. Results The ERSG signature, consisted of HSPA1A, SERPINA1, and DAPK1, could predict the prognosis of patients with COAD. Clinicopathologic characteristics were significantly correlated with risk scores. There were significant differences in the proportion of tumor-infiltrating immune cells, the TP53 mutation rate, the expression of immune checkpoint-related genes, and IC50 of the chemotherapeutic drugs between the low- and high-risk groups. Compared with normal tissues, the mRNA and protein expressions of three ERSGs were decreased in cancer tissues. Compared with NCM460, the mRNA levels of HSPA1A and DAPK1 were decreased in the majority of COAD cell lines, whereas the mRNA level of SERPINA1 was increased in HCT116 and SW480, and reduced in SW620. The ERSG signature could be used as a predictor of immunotherapeutic outcomes. Conclusion The ERSG signature has a predictive value in the prognosis and immunotherapeutic sensitivity in COAD, helping guide the personalized treatment.
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Affiliation(s)
- Lichao Cao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- Shenzhen Nucleus Gene Technology Co., Ltd., Shenzhen, China
- Shanghai Nucleus Biotechnology Co., Ltd., Shanghai, China
- Department of Research and Development, Shenzhen Nucleus Huaxi Medical Laboratory, Shenzhen, China
| | - Haoyang Dai
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- School of Medicine, Northwest University, Xi’an, China
| | - Shangqing Wei
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- School of Medicine, Northwest University, Xi’an, China
| | - Ying Ba
- Shenzhen Nucleus Gene Technology Co., Ltd., Shenzhen, China
- Shanghai Nucleus Biotechnology Co., Ltd., Shanghai, China
- Department of Research and Development, Shenzhen Nucleus Huaxi Medical Laboratory, Shenzhen, China
| | - Fang Chen
- Shenzhen Nucleus Gene Technology Co., Ltd., Shenzhen, China
- Shanghai Nucleus Biotechnology Co., Ltd., Shanghai, China
- Department of Research and Development, Shenzhen Nucleus Huaxi Medical Laboratory, Shenzhen, China
| | - Yingying Chen
- Shenzhen Nucleus Gene Technology Co., Ltd., Shenzhen, China
- Shanghai Nucleus Biotechnology Co., Ltd., Shanghai, China
- Department of Research and Development, Shenzhen Nucleus Huaxi Medical Laboratory, Shenzhen, China
| | - Chendi Yu
- Shenzhen Nucleus Gene Technology Co., Ltd., Shenzhen, China
- Shanghai Nucleus Biotechnology Co., Ltd., Shanghai, China
- Department of Research and Development, Shenzhen Nucleus Huaxi Medical Laboratory, Shenzhen, China
| | - Shenrui Zhang
- Shenzhen Nucleus Gene Technology Co., Ltd., Shenzhen, China
- Shanghai Nucleus Biotechnology Co., Ltd., Shanghai, China
- Department of Research and Development, Shenzhen Nucleus Huaxi Medical Laboratory, Shenzhen, China
| | - Erfei Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- School of Medicine, Northwest University, Xi’an, China
- Shaanxi Provincial Key Laboratory of Infection and Immune Diseases, Shaanxi Provincial People’s Hospital, Xi’an, China
| | - Hezi Zhang
- Shenzhen Nucleus Gene Technology Co., Ltd., Shenzhen, China
- Shanghai Nucleus Biotechnology Co., Ltd., Shanghai, China
- Department of Research and Development, Shenzhen Nucleus Huaxi Medical Laboratory, Shenzhen, China
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3
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D'Amato M, Iengo G, Massa N, Carlomagno C. Dihydropyrimidine dehydrogenase polymorphisms in patients with gastrointestinal malignancies and their impact on fluoropyrimidine tolerability: Experience from a single Italian institution. World J Gastrointest Oncol 2025; 17:96822. [PMID: 39817118 PMCID: PMC11664602 DOI: 10.4251/wjgo.v17.i1.96822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/14/2024] [Accepted: 08/28/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Fluoropyrimidines are metabolized in the liver by the enzyme dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. About 7% of the European population is a carrier of DPYD gene polymorphisms associated with reduced DPD enzyme activity. AIM To assess the prevalence of DPYD polymorphisms and their impact on fluoropyrimidine tolerability in Italian patients with gastrointestinal malignancies. METHODS A total of 300 consecutive patients with a diagnosis of gastrointestinal malignancy and treated with a fluoropyrimidine-based regimen were included in the analysis and divided into two cohorts: (1) 149 patients who started fluoropyrimidines after DPYD testing; and (2) 151 patients treated without DPYD testing. Among the patients in cohort A, 15% tested only the DPYD2A polymorphism, 19% tested four polymorphisms (DPYD2A, HapB3, c.2846A>T, and DPYD13), and 66% tested five polymorphisms including DPYD6. RESULTS Overall, 14.8% of patients were found to be carriers of a DPYD variant, the most common being DPYD6 (12.1%). Patients in cohort A reported ≥ G3 toxicities (P = 0.00098), particularly fewer nonhematological toxicities (P = 0.0028) compared with cohort B, whereas there was no statistically significant difference between the two cohorts in hematological toxicities (P = 0.6944). Significantly fewer chemotherapy dose reductions (P = 0.00002) were observed in cohort A compared to cohort B, whereas there was no statistically significant differences in chemotherapy delay. CONCLUSION Although this study had a limited sample size, it provides additional information on the prevalence of DPYD polymorphisms in the Italian population and highlights the role of pharmacogenetic testing to prevent severe toxicity.
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Affiliation(s)
- Mariarosaria D'Amato
- Department of Oncology, Ospedale San Rocco ASL Caserta, Sessa Aurunca 81037, Campania, Italy
| | - Gennaro Iengo
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Campania, Italy
| | - Nicola Massa
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Campania, Italy
| | - Chiara Carlomagno
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Campania, Italy
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Leung HKM, Lo EKK, Chen C, Zhang F, Felicianna, Ismaiah MJ, El-Nezami H. Probiotic Mixture Attenuates Colorectal Tumorigenesis in Murine AOM/DSS Model by Suppressing STAT3, Inducing Apoptotic p53 and Modulating Gut Microbiota. Probiotics Antimicrob Proteins 2024:10.1007/s12602-024-10405-1. [PMID: 39641861 DOI: 10.1007/s12602-024-10405-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2024] [Indexed: 12/07/2024]
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. The standard CRC chemo drug, 5-Fluorouracil (5-FU), has a poor response rate and chemoresistance, prompting the need for a more effective and affordable treatment. In this study, we aimed to evaluate whether Prohep, a novel probiotic mixture, would alleviate azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colorectal tumorigenesis and enhance 5-FU efficacy and its mechanism. Our results suggested that Prohep showed stronger anti-tumorigenesis effects than 5-FU alone or when combined in the AOM/DSS model. Prohep significantly reduced the total tumor count, total tumor size, caecum weight, colonic crypt depth, colonic inflammation, and collagen fibrosis. Prohep downregulated pro-inflammatory TNF-α and proliferative p-STAT3 and upregulated apoptotic p53. Metagenomics analysis indicated that Prohep-enriched Helicobacter ganmani, Desulfovibrio porci, Helicobacter hepaticus, and Candidatus Borkfalkia ceftriaxoniphila were inversely correlated to the total tumor count. In addition, Prohep-enriched Prevotella sp. PTAC and Desulfovibrio porci were negatively correlated to AOM/DSS enriched bacteria, while forming a co-existing community with other beneficial bacteria. From KEGG analysis, Prohep downregulated CRC-related pathways and enhanced pathways related to metabolites suppressing CRC like menaquinone, tetrapyrrole, aminolevulinic acid, and tetrahydrofolate. From Metacyc analysis, Prohep downregulated CRC-related peptidoglycan, LPS, and uric acid biosynthesis, and conversion. Prohep elevated the biosynthesis of the beneficial L-lysine, lipoic acid, pyrimidine, and palmitate. Prohep also elevated metabolic pathways related to energy utilization of lactic acid-producing bacteria (LAB) and acetate producers. Similarly, fecal acetate concentration was upregulated by Prohep. To sum up, Prohep demonstrated exceptional anti-tumorigenesis effects in the AOM/DSS model, which revealed its potential to develop into a novel CRC therapeutic in the future.
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Affiliation(s)
- Hoi Kit Matthew Leung
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, 999077, China
| | - Emily Kwun Kwan Lo
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, 999077, China
| | - Congjia Chen
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, 999077, China
| | - Fangfei Zhang
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, 999077, China
| | - Felicianna
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, 999077, China
| | - Marsena Jasiel Ismaiah
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, 999077, China
| | - Hani El-Nezami
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, 999077, China.
- Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, 70211, Kuopio, Finland.
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Taflin H, Odin E, Carlsson G, Gustavsson B, Hemmingsson O, Wettergren Y, Urbanowicz K, Turyn J, Smolenski RT, Peters GJ. Increased potentiation of 5-fluorouracil induced thymidylate synthase inhibition by 5,10-methylenetetrahydrofolate (arfolitixorin) compared to leucovorin in patients with colorectal liver metastases; The Modelle-001 Trial. BJC REPORTS 2024; 2:89. [PMID: 39567776 PMCID: PMC11579015 DOI: 10.1038/s44276-024-00111-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 10/18/2024] [Accepted: 10/20/2024] [Indexed: 11/22/2024]
Abstract
BACKGROUND 5-Fluorouracil (5-FU) is a cornerstone in treatment of colorectal cancer (CRC) and is usually combined with leucovorin (LV) to enhance the antitumour effect by increase thymidylate synthase (TS) inhibition, the key target enzyme for 5-FU. Arfolitixorin (Arfo) is an active form of the reduced folate, [6 R]-5,10-methylenetetrahydrofolate ([6 R]-MeTHF and in contrast to LV, does not need to be metabolized. The Modelle-001 was designed to explore whether a single intravenous bolus injection of Arfo as compared to LV, together with 5-FU increases the inhibition of TS, levels of folate concentrations and polyglutamylation in CRC liver metastases (CRLM) and liver parenchyma. PATIENTS AND METHODS Thirty patients with CRLM received either LV (60 mg/m2) or Arfo (30 mg/m2 or 120 mg/m2) in combination with 5-FU preoperatively. Levels of folates and and TS inhibition were measured. RESULTS Significantly higher MeTHF levels and higher TS inhibition were measured in the Arfo groups compared to LV60, and there was a difference in folate poly-glutamylation between the groups. CONCLUSION The Modelle-001 Trial demonstrated significantly higher levels of MeTHF in metastases following Arfo compared to LV. This resulted in a greater increase TS inhibition in metastases although not statistically significant.
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Grants
- CAN 2015/499, CAN 2018, CAN 201025 Swedish Cancer Society
- CAN 2015/499, CAN 2018, CAN 201025 Swedish Cancer Society
- CAN 2015/499, CAN 2018, CAN 201025 Swedish Cancer Society
- CAN 2015/499, CAN 2018, CAN 201025 Swedish Cancer Society
- ALFGBG-426941, ALFGBG-586631, ALFGBG-723361, ALFGBG-788901, ALFGBG-966007 the Swedish state under the LUA/ALF agreement
- ALFGBG-426941, ALFGBG-586631, ALFGBG-723361, ALFGBG-788901, ALFGBG-966007 the Swedish state under the LUA/ALF agreement
- ALFGBG-426941, ALFGBG-586631, ALFGBG-723361, ALFGBG-788901, ALFGBG-966007 the Swedish state under the LUA/ALF agreement
- ALFGBG-426941, ALFGBG-586631, ALFGBG-723361, ALFGBG-788901, ALFGBG-966007 the Swedish state under the LUA/ALF agreement
- 335/07 IngaBritt and Arne Lundberg Foundation
- 335/07 IngaBritt and Arne Lundberg Foundation
- 335/07 IngaBritt and Arne Lundberg Foundation
- 335/07 IngaBritt and Arne Lundberg Foundation
- unconditional grant Isofol Medical AB
- Swedish Society of Medicine
- The Gothenburg Society of Medicine
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Affiliation(s)
- Helena Taflin
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
- Region Västra Götaland, Sahlgrenska University Hospital, Department of Surgery, Gothenburg, Sweden.
| | - Elisabeth Odin
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Sahlgrenska University Hospital, Department of Surgery, Gothenburg, Sweden
| | - Göran Carlsson
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Sahlgrenska University Hospital, Department of Surgery, Gothenburg, Sweden
| | - Bengt Gustavsson
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Sahlgrenska University Hospital, Department of Surgery, Gothenburg, Sweden
| | - Oskar Hemmingsson
- Department of Diagnostics and Intervention/Surgery, Umeå University, Umeå, Sweden
| | - Yvonne Wettergren
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Sahlgrenska University Hospital, Department of Surgery, Gothenburg, Sweden
| | | | - Jacek Turyn
- Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
| | | | - Godefridus J Peters
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (Amsterdam UMC), Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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Chen M, Ma S, Ji W, Hu W, Gao J, Yang J, Liu Y, Cui Q, Yang S, Xu X, Dai H, Hu L. Shenqi Sanjie Granules induce Hmox1-mediated ferroptosis to inhibit colorectal cancer. Heliyon 2024; 10:e38021. [PMID: 39347400 PMCID: PMC11437928 DOI: 10.1016/j.heliyon.2024.e38021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/04/2024] [Accepted: 09/16/2024] [Indexed: 10/01/2024] Open
Abstract
Background Because adverse reactions or drug resistance are often found after current chemotherapies for metastatic colorectal cancer (mCRC), new treatments are still in demand. Shenqi Sanjie Granules (SSG), an antitumor compound preparation of traditional Chinese medicine, has been recognized for its ability in clinical practice of oncotherapy. Nevertheless, the precise effects of SSG in colorectal cancer (CRC) and underlying mechanisms through which SSG inhibits CRC remain uncertain. The current study aimed to evaluate the anti-CRC activity of the Chinese herbal compound preparation SSG and investigate the underlying mechanisms of action. Materials and methods Initially, nine distinct cancer cell lines, including five CRC cell lines, one breast cancer cell line, two lung adenocarcinoma cell lines and one cervical cancer cell line, were used to evaluate the antitumor activity of SSG, and the mouse CRC cell line CT26 were used for further research. In vitro experiments utilizing diverse assays were conducted to assess the inhibitory effects of the SSG on CT26. Furthermore, subcutaneous syngeneic mouse model and AOM (azoxymethane)/DSS (dextran sodium sulfate) induced in-situ colitis-related mouse CRC model were used to evaluate the antitumor potential and biotoxicity of SSG in vivo. To elucidate the underlying molecular mechanisms, transcriptome sequencing and network pharmacology analysis were performed. Meanwhile, verification is carried out with quantitative real-time PCR (qRT-PCR) and flow cytometry (FCM) analysis. Results Our in vitro inhibition study showed that SSG could effectively inhibit CRC cell line CT26 growth and metastasis, and induce cell death. Neither of apoptosis inhibitor, necroptosis inhibitor, ferroptosis inhibitor, but the combination of the three diminished SSG-induced cell death, suggesting that multiple cell death pathways were involved. Both the syngeneic CRC model and the in-situ CRC model indicated SSG inhibited CRC in vivo with few toxic side effects. Further mechanistic study suggested SSG treatment activated the ferroptosis pathway, particularly mediated by Hmox1, which was upregulated scores of times. Network pharmacology analysis indicated that the active ingredients of SSG, including Quercetin, Luteolin and Kaempferol were potential components directly upregulated Hmox1 expression. Conclusions Collectively, our findings indicate that the administration of SSG has the potential to inhibit CRC both in vitro and in vivo. The mechanism by which this compound preparation exerts its action is, at least partly, the induction of ferroptosis through upregulating Hmox-1 by its three active ingredients Quercetin, Luteolin and Kaempferol.
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Affiliation(s)
- Meng Chen
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, 241002, China
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Shengli Ma
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, 241002, China
| | - Wenbo Ji
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230026, China
| | - Weihua Hu
- Reproductive Medicine Center, the First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China
| | - Jiguang Gao
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, 241002, China
| | - Jianke Yang
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, 241002, China
| | - Yu Liu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230026, China
| | - Qianwen Cui
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230026, China
| | - Shasha Yang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Xiaohui Xu
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, 241002, China
| | - Haiming Dai
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230026, China
| | - Lei Hu
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, 241002, China
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
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Qin YT, Liu X, An JX, Chen Z, Niu MT, Yan X, Li QR, Rao ZY, Zhang XZ. Oral Saccharomyces cerevisiae-Guided Enzyme Prodrug Therapy Combined with Immunotherapy for the Treatment of Orthotopic Colorectal Cancer. ACS NANO 2024; 18:23497-23507. [PMID: 39146387 DOI: 10.1021/acsnano.4c07115] [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: 08/17/2024]
Abstract
Colorectal cancer (CRC) is a major global health concern, and the development of effective treatment strategies is crucial. Enzyme prodrug therapy (EPT) shows promise in combating tumors but faces challenges in achieving sustained expression of therapeutic enzymes and optimal biological distribution. To address these issues, a fungi-triggered in situ chemotherapeutics generator (named as SC@CS@5-FC) was constructed via oral delivery of a prodrug (5-fluorocytosine, 5-FC) for the treatment of orthotopic colorectal tumor. When SC@CS@5-FC targets the tumor through tropism by Saccharomyces cerevisiae (SC), the chemotherapeutic generator could be degraded under abundant hyaluronidase (HAase) in the tumor microenvironment by an enzyme-responsive gate to release prodrug (5-FC). And nontoxic 5-FC was catalyzed to toxic chemotherapy drug 5-fluorouracil (5-FU) by cytosine deaminase (CD) of SC. Meanwhile, SC and zinc-coordinated chitosan nanoparticles could be used as immune adjuvants to activate antigen-presenting cells and further enhance the therapeutic effect. Our results demonstrated that SC@CS@5-FC could effectively inhibit tumor growth and prolong mouse survival in an orthotopic colorectal cancer model. This work utilizes living SC as a dynamotor and positioning system for the chemotherapeutic generator SC@CS@5-FC, providing a strategy for oral enzyme prodrug therapy for the treatment of orthotopic colorectal.
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Affiliation(s)
- You-Teng Qin
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, PR China
| | - Xinhua Liu
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, PR China
| | - Jia-Xin An
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, PR China
| | - Zhu Chen
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, PR China
| | - Mei-Ting Niu
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, PR China
| | - Xiao Yan
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, PR China
| | - Qian-Ru Li
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, PR China
| | - Zhi-Yong Rao
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, PR China
| | - Xian-Zheng Zhang
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, PR China
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8
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Peters GJ, Kathmann I, Giovannetti E, Smid K, Assaraf YG, Jansen G. The role of l-leucovorin uptake and metabolism in the modulation of 5-fluorouracil efficacy and antifolate toxicity. Front Pharmacol 2024; 15:1450418. [PMID: 39234107 PMCID: PMC11371747 DOI: 10.3389/fphar.2024.1450418] [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: 06/17/2024] [Accepted: 07/30/2024] [Indexed: 09/06/2024] Open
Abstract
BACKGROUND L-Leucovorin (l-LV; 5-formyltetrahydrofolate, folinic acid) is a precursor for 5,10-methylenetetrahydrofolate (5,10-CH2-THF), which is important for the potentiation of the antitumor activity of 5-fluorouracil (5FU). LV is also used to rescue antifolate toxicity. LV is commonly administered as a racemic mixture of its l-LV and d-LV stereoisomers. We compared dl-LV with l-LV and investigated whether d-LV would interfere with the activity of l-LV. METHODS Using radioactive substrates, we characterized the transport properties of l-LV and d-LV, and compared the efficacy of l-LV with d-LV to potentiate 5FU-mediated thymidylate synthase (TS) inhibition. Using proliferation assays, we investigated their potential to protect cancer cells from cytotoxicity of the antifolates methotrexate, pemetrexed (Alimta), raltitrexed (Tomudex) and pralatrexate (Folotyn). RESULTS l-LV displayed an 8-fold and 3.5-fold higher substrate affinity than d-LV for the reduced folate carrier (RFC/SLC19A1) and proton coupled folate transporter (PCFT/SLC46A1), respectively. In selected colon cancer cell lines, the greatest enhanced efficacy of 5FU was observed for l-LV (2-fold) followed by the racemic mixture, whereas d-LV was ineffective. The cytotoxicity of antifolates in lymphoma and various solid tumor cell lines could be protected very efficiently by l-LV but not by d-LV. This protective effect of l-LV was dependent on cellular RFC expression as corroborated in RFC/PCFT-knockout and RFC/PCFT-transfected cells. Assessment of TS activity in situ showed that TS inhibition by 5FU could be enhanced by l-LV and dl-LV and only partially by d-LV. However, protection from inhibition by various antifolates was solely achieved by l-LV and dl-LV. CONCLUSION In general l-LV acts similar to the dl-LV formulations, however disparate effects were observed when d-LV and l-LV were used in combination, conceivably by d-LV affecting (anti)folate transport and intracellular metabolism.
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Affiliation(s)
- Godefridus J. Peters
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
| | - Ietje Kathmann
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, Pisa, Italy
| | - Kees Smid
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Yehuda G. Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, The Technion-Israel Institute of Technology, Haifa, Israel
| | - Gerrit Jansen
- Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
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9
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Zhang M, Hu T, Ma T, Huang W, Wang Y. Epigenetics and environmental health. Front Med 2024; 18:571-596. [PMID: 38806988 DOI: 10.1007/s11684-023-1038-2] [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: 07/03/2023] [Accepted: 10/15/2023] [Indexed: 05/30/2024]
Abstract
Epigenetic modifications including DNA methylation, histone modifications, chromatin remodeling, and RNA modifications complicate gene regulation and heredity and profoundly impact various physiological and pathological processes. In recent years, accumulating evidence indicates that epigenetics is vulnerable to environmental changes and regulates the growth, development, and diseases of individuals by affecting chromatin activity and regulating gene expression. Environmental exposure or induced epigenetic changes can regulate the state of development and lead to developmental disorders, aging, cardiovascular disease, Alzheimer's disease, cancers, and so on. However, epigenetic modifications are reversible. The use of specific epigenetic inhibitors targeting epigenetic changes in response to environmental exposure is useful in disease therapy. Here, we provide an overview of the role of epigenetics in various diseases. Furthermore, we summarize the mechanism of epigenetic alterations induced by different environmental exposures, the influence of different environmental exposures, and the crosstalk between environmental variation epigenetics, and genes that are implicated in the body's health. However, the interaction of multiple factors and epigenetics in regulating the initiation and progression of various diseases complicates clinical treatments. We discuss some commonly used epigenetic drugs targeting epigenetic modifications and methods to prevent or relieve various diseases regulated by environmental exposure and epigenetics through diet.
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Affiliation(s)
- Min Zhang
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ting Hu
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tianyu Ma
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Wei Huang
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
| | - Yan Wang
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
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10
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Hu Y, Du Y, Qiu Z, Zhu C, Wang J, Liang T, Liu T, Da M. Signal mining and analysis of trifluridine/tipiracil adverse events based on real-world data from the FAERS database. Front Pharmacol 2024; 15:1399998. [PMID: 39108741 PMCID: PMC11301057 DOI: 10.3389/fphar.2024.1399998] [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: 03/12/2024] [Accepted: 06/26/2024] [Indexed: 01/03/2025] Open
Abstract
OBJECTIVE The objective of this research is to scrutinize adverse events (AEs) linked to Trifluridine/Tipiracil (TFTD/TPI), using data from the FDA Adverse Event Reporting System (FAERS) database. METHODS The AEs data related to TFTD/TPI were collected from the fourth quarter of 2015 through the fourth quarter of 2023. After normalizing the data, multiple signal quantification techniques including Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), Bayesian approaches such as Bayesian Confidence Propagation Neural Network (BCPNN) and the Multi-item Gamma Poisson Shrinker (MGPS) were used for overall and subgroup analysis and visualization analyses were performed. RESULTS From the FAERS database, we analyzed 13,520,073 reports, identifying 8,331 as primary suspect (PS) AEs for TFTD/TPI, occurring across 27 organ systems. The study retained 99 significant disproportionality Preferred Terms (PTs) across four algorithms and unveiled unexpected serious AEs such as iron deficiency and intestinal perforation, hepatic failure, cholangitis and so on. The median onset of TFTD/TPI-associated AEs was 44 days (IQR 20-97 days), with most occurring within the first 30 days of treatment. CONCLUSION This research uncovers critical new safety signals for TFTD/TPI, supporting its clinical monitoring and risk identification.
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Affiliation(s)
- Yongli Hu
- The First Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou, China
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Yan Du
- The Second Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou, China
| | - Zhisheng Qiu
- Department of Oncology Surgery, Gansu Provincial Hospital, Lanzhou, China
| | - Chenglou Zhu
- The First Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou, China
| | - Junhong Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou, China
| | - Tong Liang
- The First Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou, China
| | - Tianxiang Liu
- Department of Oncology Surgery, Gansu Provincial Hospital, Lanzhou, China
| | - Mingxu Da
- The First Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou, China
- Department of Oncology Surgery, Gansu Provincial Hospital, Lanzhou, China
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11
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Tabernero J, Yoshino T, Stintzing S, de Gramont A, Gibbs P, Jonker DJ, Nygren P, Papadimitriou C, Prager GW, Tell R, Lenz HJ. A Randomized Phase III Study of Arfolitixorin versus Leucovorin with 5-Fluorouracil, Oxaliplatin, and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer: The AGENT Trial. CANCER RESEARCH COMMUNICATIONS 2024; 4:28-37. [PMID: 38059497 PMCID: PMC10765772 DOI: 10.1158/2767-9764.crc-23-0361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/24/2023] [Accepted: 12/01/2023] [Indexed: 12/08/2023]
Abstract
PURPOSE Suboptimal treatment outcomes with 5-fluorouracil (5-FU)/folate, the standard of care for metastatic colorectal cancer (mCRC), have generated interest in optimizing the folate. Arfolitixorin ([6R]-5,10-methylene-tetrahydrofolate) is an immediately active folate and may improve outcomes over the existing standard of care (leucovorin). EXPERIMENTAL DESIGN AGENT was a randomized, phase III study (NCT03750786). Patients with mCRC were randomized to arfolitixorin (120 mg/m2 given as two intravenous bolus doses of 60 mg/m2) or leucovorin (400 mg/m2 given as a single intravenous infusion) plus 5-FU, oxaliplatin, and bevacizumab. Assessments were performed every 8 weeks. The primary endpoint was the superiority of arfolitixorin for overall response rate (ORR). RESULTS Between February 2019 and April 2021, 490 patients were randomized (245 to each arm). After a median follow-up of 266 days, the primary endpoint of superiority for ORR was not achieved (48.2% for arfolitixorin vs. 49.4% for leucovorin, Psuperiority = 0.57). Outcomes were not achieved for median progression-free survival (PFS; 12.8 and 11.6 months, P = 0.38), median duration of response (12.2 and 12.9 months, P = 0.40), and median overall survival (23.8 and 28.0 months, P = 0.78). The proportion of patients with an adverse event of grade ≥3 severity was similar between arms (68.7% and 67.2%, respectively), as was quality of life. BRAF mutations and MTHFD2 expression were both associated with a lower PFS with arfolitixorin. CONCLUSIONS The study failed to demonstrate clinical benefit of arfolitixorin (120 mg/m2) over leucovorin. However, it provides some useful insights from the first-line treatment setting, including the effect of gene expression on outcomes. SIGNIFICANCE This phase III study compared arfolitixorin, a direct-acting folate, with leucovorin in FOLFOX plus bevacizumab in mCRC. Arfolitixorin (120 mg/m2) did not improve the ORR, potentially indicating a suboptimal dose.
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Affiliation(s)
- Josep Tabernero
- Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, Barcelona, Spain
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Sebastian Stintzing
- Department of Hematology, Oncology and Cancer Immunology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Aimery de Gramont
- Institute Hospitalier Franco-Britannique, Oncologie médicale, Levallois-Perret, France
| | - Peter Gibbs
- Western Health – Sunshine Hospital, Medical Oncology, St. Albans, Victoria, Australia
| | - Derek J. Jonker
- Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada
| | - Peter Nygren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Christos Papadimitriou
- Oncology Unit, “Aretaieion” University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | - Heinz-Josef Lenz
- Division of Medical Oncology and Colorectal Cancer, Keck School of Medicine, University of Southern California, Los Angeles, California
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12
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Li XJ, Nie P, Herdewijn P, Sun JG. Unlocking the synthetic approaches and clinical application of approved small-molecule drugs for gastrointestinal cancer treatment: A comprehensive exploration. Eur J Med Chem 2023; 262:115928. [PMID: 37944387 DOI: 10.1016/j.ejmech.2023.115928] [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: 10/15/2023] [Revised: 10/29/2023] [Accepted: 10/31/2023] [Indexed: 11/12/2023]
Abstract
Gastrointestinal (GI) cancers encompass a group of malignancies affecting the digestive system, including the stomach, esophagus, liver, colon, rectum and pancreas. These cancers represent a significant global health burden, necessitating effective treatment strategies. Small-molecule drugs have emerged as crucial therapeutic options in the fight against GI cancers due to their oral bioavailability, targeted mechanisms of action, and well-established safety profiles. The review then elucidates the clinical applications and synthetic methods of clinically approved small-molecule drugs for the treatment of GI cancer, shedding light on their mechanisms of action and their potential in mitigating GI cancer progression. The review also discusses future prospects and the evolving landscape of small-molecule drug development in GI oncology, highlighting the potential for personalized medicine. In summary, this review provides valuable insights into cutting-edge strategies for harnessing clinically approved small-molecule drugs to combat GI cancer effectively.
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Affiliation(s)
- Xiao-Jing Li
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Peng Nie
- Medicinal Chemistry, Rega Institute of Medical Research, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
| | - Piet Herdewijn
- Medicinal Chemistry, Rega Institute of Medical Research, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
| | - Jian-Gang Sun
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
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13
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Marabada D, Li J, Wei S, Huang Q, Wang Z. Cyclodextrin based nanoparticles for smart drug delivery in colorectal cancer. Chem Biol Drug Des 2023; 102:1618-1631. [PMID: 37705133 DOI: 10.1111/cbdd.14344] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/24/2023] [Accepted: 08/30/2023] [Indexed: 09/15/2023]
Abstract
The advancement of colorectal cancer (CRC) prevention, detection, and treatment is essential to ensure that survivors live longer and higher-quality lives. The field of cancer detection and therapy has undergone a revolution with the development of nanotechnology for targeted drug delivery. The significant problems with the delivery of cancer drugs are their solubility, stability, and nonspecific distribution. There is a challenge that the acidic and enzymatic environment in the digestive tract will modify or destroy the medication or the active pharmaceutical ingredient. To overcome the problems, nanoparticles have been widely employed during the past several years to increase the specificity, selectivity, and controlled release of drug delivery systems. The site-specific and targeted delivery leads to reduce toxicity and side effects. With respect to the capability and utilization of cyclodextrin-based nanoparticles in different aspects of the tumour microenvironment and gut microbiota, a survey of current research papers was conducted via looking through databases including GoogleScholar, PubMed, Web of Science, and Scopus. This review aims to summarize cutting-edge nanoparticulate-based technologies and therapies for CRC.
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Affiliation(s)
- Davies Marabada
- School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Jinlei Li
- School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Shijie Wei
- General Hospital, Ningxia Medical University, Yinchuan, China
| | - Qing Huang
- School of Pharmacy, Ningxia Medical University, Yinchuan, China
- Key Laboratory of Ningxia Minority Medicine Modernization, Ministry of Education, Yinchuan, China
| | - Zhizhong Wang
- School of Pharmacy, Ningxia Medical University, Yinchuan, China
- Key Laboratory of Ningxia Minority Medicine Modernization, Ministry of Education, Yinchuan, China
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14
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Chen L, Zhao R, Kang Z, Cao Z, Liu N, Shen J, Wang C, Pan F, Zhou X, Liu Z, Yang Y, Chen Q. Delivery of short chain fatty acid butyrate to overcome Fusobacterium nucleatum-induced chemoresistance. J Control Release 2023; 363:43-56. [PMID: 37734673 DOI: 10.1016/j.jconrel.2023.09.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 09/10/2023] [Accepted: 09/17/2023] [Indexed: 09/23/2023]
Abstract
The gut microbiota is closely associated with the progression of colorectal cancer (CRC) in which Fusobacterium nucleatum (F. nucleatum) was found to induce cancer resistance to chemotherapeutics. To relieve F. nucleatum-induced drug resistance, herein, we found that short-chain fatty acid butyrate can inhibit the growth, enrichment and adhesion of F. nucleatum in colorectal cancer tissues by downregulating the expression of adhesion-associated outer membrane proteins, including RadD, FomA, and FadA, to reduce the colonization and invasion of F. nucleatum and relieve the chemoresistance induced by F. nucleatum. Leveraging the killing effect of butyrate on F. nucleatum, sodium butyrate (NaBu) was encapsulated in liposomes or prepared as NaBu tablets with Eudragit S100 coating and administered by intravenous injection or oral administration, respectively. Interestingly, both intravenous administration of NaBu liposomes and oral delivery of NaBu tablets could effectively inhibit the proliferation of F. nucleatum and significantly improve the therapeutic efficacy of oxaliplatin in mice with subcutaneous colorectal tumors, orthotopic colorectal tumors and even spontaneously formed colorectal tumors. Thus, our work provides a simple but effective formulation of NaBu to relieve F. nucleatum-induced chemoresistance, exhibiting ideal clinical application prospects.
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Affiliation(s)
- Linfu Chen
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, PR China
| | - Rui Zhao
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, PR China
| | - Zheyu Kang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, PR China
| | - Zhiqin Cao
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, PR China
| | - Nanhui Liu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, PR China
| | - Jingjing Shen
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, PR China
| | - Cheng Wang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, PR China
| | - Feng Pan
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, PR China
| | - Xiao Zhou
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, PR China
| | - Zhuang Liu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, PR China
| | - Yang Yang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, PR China
| | - Qian Chen
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, PR China.
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15
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Chen L, Sun K, Qin W, Huang B, Wu C, Chen J, Lai Q, Wang X, Zhou R, Li A, Liu S, Zhang Y. LIMK1 m 6A-RNA methylation recognized by YTHDC2 induces 5-FU chemoresistance in colorectal cancer via endoplasmic reticulum stress and stress granule formation. Cancer Lett 2023; 576:216420. [PMID: 37778684 DOI: 10.1016/j.canlet.2023.216420] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/06/2023] [Accepted: 09/29/2023] [Indexed: 10/03/2023]
Abstract
LIM kinase 1 (LIMK1) is a member of the LIMK family that has been considered to be involved in chemoresistance in various tumors, and N6-methyladenosine (m6A) is the most abundant nucleotide modification on mRNA. However, whether elevated expression of LIMK1 leads to chemoresistance due to m6A modification remains to be further studied. The findings of our study indicate that high LIMK1 expression in colorectal cancer (CRC) cells promotes cell proliferation and increases resistance to 5-fluorouracil (5-FU). Moreover, downregulation of YTH domain-containing 2 (YTHDC2), an m6A "reader", in CRC cells resulted in decreased recognition and binding to the m6A site "GGACA" in LIMK1 mRNA, thereby increasing LIMK1 mRNA stability and expression. Furthermore, the overexpression of LIMK1 facilitated eIF2α phosphorylation, which induced endoplasmic reticulum (ER) stress and promoted stress granule (SG) formation, ultimately leading to 5-FU resistance. This study evaluated the specificity of the YTHDC2/LIMK1/eIF2α signalling axis and the efficacy of related drugs in modulating 5-FU sensitivity in CRC.
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Affiliation(s)
- Lu Chen
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kangyue Sun
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wenjie Qin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bing Huang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Changjie Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Junsheng Chen
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qiuhua Lai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xinke Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rui Zhou
- Guangdong Province Key Laboratory of Molecular Tumor Pathology, Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Aimin Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Side Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Gastroenterology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China.
| | - Yue Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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16
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Blachman A, Birocco AM, Curcio S, Camperi SA, Gianvincenzo PD, Rodriguez JA, Barredo-Vacchelli GR, Cenci G, Sosnik A, Moya S, Calabrese GC. Dermatan Sulfate/Chitosan Nanoparticles Loaded with an Anti-Inflammatory Peptide Increase the Response of Human Colorectal Cancer Cells to 5-Fluorouracil. Macromol Biosci 2023; 23:e2300193. [PMID: 37469233 DOI: 10.1002/mabi.202300193] [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: 05/05/2023] [Revised: 06/24/2023] [Accepted: 07/18/2023] [Indexed: 07/21/2023]
Abstract
The gold standard drug for colorectal cancer (CRC) treatment, 5-Fluorouracil (5-FU), induces pharmacological tolerance in long-term management. The transcriptional factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) plays a key role in 5-FU resistance. The aim of this work is to study the capability of polyelectrolytes complex nanoparticles of dermatan sulfate (DS) and chitosan (CS), loaded with the anti-inflammatory tripeptide IRW, to sensitize colorectal cancer cells to 5-FU. Fluorescence and flow cytometry studies confirmed the recognition by the nanoformulation, of the cluster of differentiation 44 (CD44) receptor, involved in the initiation and progression of colorectal tumors. Dynamic light scattering (DLS) and flow cytometry reinforced the importance of DS and CD44 receptor in the interaction, as the addition of DS or anti-CD44 antibody blocked the binding. Moreover, the nanoformulation also interacts with 3D colon cancer cultures, namely colonospheres, enriched in cancer stem cells (CSC), subpopulation responsible for drug resistance and metastasis. To evaluate the consequences of this interaction, the subcellular distribution of the transcriptional factor NFκB, is determined by immunofluorescence analysis. Internalization and the intracellular release of IRW inhibited nuclear translocation of NFκB and increased cellular sensitivity to 5-FU. Altogether, the nanoformulation could provide a selective delivery platform for IRW distribution to colorectal tumors, being an innovative strategy toward overcoming 5-FU resistance in CRC therapy.
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Affiliation(s)
- Agustín Blachman
- Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), UBA- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Junín 956, C1113AAD Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Ariadna María Birocco
- Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), UBA- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Junín 956, C1113AAD Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Sofía Curcio
- Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), UBA- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Junín 956, C1113AAD Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Biotecnología. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Nanobiotecnología (NANOBIOTEC), Junín 956, C1113AAD, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Silvia Andrea Camperi
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Biotecnología. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Nanobiotecnología (NANOBIOTEC), Junín 956, C1113AAD, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Paolo Di Gianvincenzo
- Soft Matter Nanotechnology, Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo Miramon 182 C, Donostia, San Sebastián, 20014, Spain
| | - Jésica Ayelén Rodriguez
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Biotecnología. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Nanobiotecnología (NANOBIOTEC), Junín 956, C1113AAD, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Gabriela Romina Barredo-Vacchelli
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Biotecnología. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Nanobiotecnología (NANOBIOTEC), Junín 956, C1113AAD, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Gloria Cenci
- Soft Matter Nanotechnology, Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo Miramon 182 C, Donostia, San Sebastián, 20014, Spain
| | - Alejandro Sosnik
- Laboratory of Pharmaceutical Nanomaterials Science, Department of Materials Science and Engineering Technion-Israel Institute of Technology, Technion City, Haifa, 3200003, Israel
| | - Sergio Moya
- Soft Matter Nanotechnology, Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo Miramon 182 C, Donostia, San Sebastián, 20014, Spain
| | - Graciela Cristina Calabrese
- Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), UBA- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Junín 956, C1113AAD Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
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Wang H, Li Z, Tao Y, Ou S, Ye J, Ran S, Luo K, Guan Z, Xiang J, Yan G, Wang Y, Ma T, Yu S, Song Y, Huang R. Characterization of endoplasmic reticulum stress unveils ZNF703 as a promising target for colorectal cancer immunotherapy. J Transl Med 2023; 21:713. [PMID: 37821882 PMCID: PMC10566095 DOI: 10.1186/s12967-023-04547-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 09/20/2023] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common malignant tumors globally, with high morbidity and mortality. Endoplasmic reticulum is a major organelle responsible for protein synthesis, processing, and transport. Endoplasmic reticulum stress (ERS) refers to the abnormal accumulation of unfolded and misfolded proteins in the endoplasmic reticulum, which are involved in tumorigenesis and cancer immunity. Nevertheless, the clinical significance of ERS remains largely unexplored in CRC. METHODS In present study, we performed an unsupervised clustering to identify two types of ERS-related subtypes [ERS clusters, and ERS-related genes (ERSGs) clusters] in multiple large-scale CRC cohorts. Through the utilization of machine learning techniques, we have successfully developed an uncomplicated yet robust gene scoring system (ERSGs signature). Furthermore, a series of analyses, including GO, KEGG, Tumor Immune Dysfunction and Exclusion (TIDE), the Consensus Molecular Subtypes (CMS), were used to explore the underlying biological differences and clinical significance between these groups. And immunohistochemical and bioinformatics analyses were performed to explore ZNF703, a gene of ERSGs scoring system. RESULTS We observed significant differences in prognosis and tumor immune status between the ERS clusters as well as ERSGs clusters. And the ERSGs scoring system was an independent risk factor for overall survival; and exhibited distinct tumor immune status in multicenter CRC cohorts. Besides, analyses of TNM stages, CMS groups demonstrated that patients in advanced stage and CMS4 had higher ERSGs scores. In addition, the ERSGs scores inversely correlated with positive ICB response predictors (such as, CD8A, CD274 (PD-L1), and TIS), and directly correlated with negative ICB response predictors (such as, TIDE, T cell Exclusion, COX-IS). Notably, immunohistochemical staining and bioinformatics analyses revealed that ZNF70 correlated with CD3 + and CD8 + T cells infiltration. CONCLUSION Based on large-scale and multicenter transcriptomic data, our study comprehensively revealed the essential role of ERS in CRC; and constructed a novel ERSGs scoring system to predict the prognosis of patients and the efficacy of ICB treatment. Furthermore, we identified ZNF703 as a potentially promising target for ICB therapy in CRC.
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Affiliation(s)
- Hufei Wang
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150080, China
| | - Zhi Li
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yangbao Tao
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150080, China
| | - Suwen Ou
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150080, China
| | - Jinhua Ye
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150080, China
| | - Songlin Ran
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150080, China
| | - Kangjia Luo
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150080, China
| | - Zilong Guan
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150080, China
| | - Jun Xiang
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150080, China
| | - Guoqing Yan
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150080, China
| | - Yang Wang
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150080, China
| | - Tianyi Ma
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150080, China
| | - Shan Yu
- Department of Pathology, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150080, China.
| | - Yanni Song
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
| | - Rui Huang
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150080, China.
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18
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Hu S, Xia K, Huang X, Zhao Y, Zhang Q, Huang D, Xu W, Chen Z, Wang C, Zhang Z. Multifunctional CaCO 3@Cur@QTX125@HA nanoparticles for effectively inhibiting growth of colorectal cancer cells. J Nanobiotechnology 2023; 21:353. [PMID: 37773145 PMCID: PMC10543835 DOI: 10.1186/s12951-023-02104-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 09/11/2023] [Indexed: 10/01/2023] Open
Abstract
Colorectal cancer (CRC) is a major cause of cancer-related deaths in humans, and effective treatments are still needed in clinical practice. Despite significant developments in anticancer drugs and inhibitors, their poor stability, water solubility, and cellular membrane permeability limit their therapeutic efficacy. To address these issues, multifunctional CaCO3 nanoparticles loaded with Curcumin (Cur) and protein deacetylase (HDAC) inhibitor QTX125, and coated with hyaluronic acid (HA) (CaCO3@Cur@QTX125@HA), were prepared through a one-step gas diffusion strategy. Dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) showed that CaCO3@Cur@QTX125@HA nanoparticles have uniform spherical morphology and elemental distribution, with diameters around 450 nm and a Zeta potential of - 8.11 mV. The controlled release of Cur from the nanoparticles was observed over time periods of 48 h. Cellular uptake showed that CaCO3@Cur@QTX125@HA nanoparticles were efficiently taken up by cancer cells and significantly inhibited their growth. Importantly, CaCO3@Cur@QTX125@HA nanoparticles showed specific inhibitory effects on CRC cell growth. Encouragingly, CaCO3@Cur@QTX125@HA nanoparticles successfully internalized into CRC patient-derived organoid (PDO) models and induced apoptosis of tumor cells. The multifunctional CaCO3@Cur@QTX125@HA nanoparticles hold promise for the treatment of CRC.
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Affiliation(s)
- Shengyun Hu
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Kunkun Xia
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xiaobei Huang
- Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, 400714, China
| | - Ye Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Qingqing Zhang
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Dongdong Huang
- Pooling Medical Research Institutes of 100Biotech, Beijing, 100006, China
| | - Weiyi Xu
- Department of Dermatology, National Children's Medical Center, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Zhengju Chen
- Pooling Medical Research Institutes of 100Biotech, Beijing, 100006, China.
| | - Chenfei Wang
- Department of Dermatology, National Children's Medical Center, Children's Hospital of Fudan University, Shanghai, 201102, China.
| | - Zhiyong Zhang
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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He X, Lan H, Jin K, Liu F. Can immunotherapy reinforce chemotherapy efficacy? a new perspective on colorectal cancer treatment. Front Immunol 2023; 14:1237764. [PMID: 37790928 PMCID: PMC10543914 DOI: 10.3389/fimmu.2023.1237764] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/25/2023] [Indexed: 10/05/2023] Open
Abstract
As one of the main threats to human life (the fourth most dangerous and prevalent cancer), colorectal cancer affects many people yearly, decreases patients' quality of life, and causes irreparable financial and social damages. In addition, this type of cancer can metastasize and involve the liver in advanced stages. However, current treatments can't completely eradicate this disease. Chemotherapy and subsequent surgery can be mentioned among the current main treatments for this disease. Chemotherapy has many side effects, and regarding the treatment of this type of tumor, chemotherapy can lead to liver damage, such as steatohepatitis, steatosis, and sinus damage. These damages can eventually lead to liver failure and loss of its functions. Therefore, it seems that other treatments can be used in addition to chemotherapy to increase its efficiency and reduce its side effects. Biological therapies and immunotherapy are one of the leading suggestions for combined treatment. Antibodies (immune checkpoint blockers) and cell therapy (DC and CAR-T cells) are among the immune system-based treatments used to treat tumors. Immunotherapy targets various aspects of the tumor that may lead to 1) the recruitment of immune cells, 2) increasing the immunogenicity of tumor cells, and 3) leading to the elimination of inhibitory mechanisms established by the tumor. Therefore, immunotherapy can be used as a complementary treatment along with chemotherapy. This review will discuss different chemotherapy and immunotherapy methods for colorectal cancer. Then we will talk about the studies that have dealt with combined treatment.
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Affiliation(s)
- Xing He
- Department of Gastroenterology, Jinhua Wenrong Hospital, Jinhua, Zhejiang, China
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Fanlong Liu
- Department of Colorectal Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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20
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Huang S, Ye J, Gao X, Huang X, Huang J, Lu L, Lu C, Li Y, Luo M, Xie M, Lin Y, Liang R. Progress of research on molecular targeted therapies for colorectal cancer. Front Pharmacol 2023; 14:1160949. [PMID: 37614311 PMCID: PMC10443711 DOI: 10.3389/fphar.2023.1160949] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 07/26/2023] [Indexed: 08/25/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies, accounting for approximately 10% of global cancer incidence and mortality. Approximately 20% of patients with CRC present metastatic disease (mCRC) at the time of diagnosis. Moreover, up to 50% of patients with localized disease eventually metastasize. mCRC encompasses a complex cascade of reactions involving multiple factors and processes, leading to a diverse array of molecular mechanisms. Improved comprehension of the pathways underlying cancer cell development and proliferation, coupled with the accessibility of relevant targeted agents, has propelled advancements in CRC treatment, ultimately leading to enhanced survival rates. Mutations in various pathways and location of the primary tumor in CRC influences the efficacy of targeted agents. This review summarizes available targeted agents for different CRC pathways, with a focus on recent advances in anti-angiogenic and anti-epidermal growth factor receptor agents, BRAF mutations, and human epidermal growth factor receptor 2-associated targeted agents.
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Affiliation(s)
- Shilin Huang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jiazhou Ye
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xing Gao
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xi Huang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Julu Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Lu Lu
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Cheng Lu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yongqiang Li
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Min Luo
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Mingzhi Xie
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yan Lin
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Rong Liang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
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21
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Voutsadakis IA. High tumor mutation burden (TMB) in microsatellite stable (MSS) colorectal cancers: Diverse molecular associations point to variable pathophysiology. Cancer Treat Res Commun 2023; 36:100746. [PMID: 37494750 DOI: 10.1016/j.ctarc.2023.100746] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/16/2023] [Accepted: 07/20/2023] [Indexed: 07/28/2023]
Abstract
BACKGROUND Colorectal cancers with defects in the Mismatch Repair (MMR) system represent a minority of the disease. MMR defective cancers are characterized by high Tumor Mutation Burden (TMB) and are sensitive to immunotherapy with immune checkpoint inhibitors. In contrast, the majority of colorectal cancers are MMR proficient (Microsatellite Stable, MSS) and display a low TMB. However, a few of these MSS cancers have high TMB. METHODS Published genomic studies of colorectal cancers were examined to identify cases profiled as MSS and having a TMB above 10 mutations / Mb. Data from four studies detailed in the cBioportal for cancer genomics site and providing data on MSI status were examined. RESULTS In the MSK study of metastatic colorectal cancers, 7.5% of patients with MSS tumors had a high TMB of more than 10 mutations/ Mb. The MSK study of localized rectal cancers showed that 9.5% of patients with MSS tumors had a high TMB. The DFCI cohort included 10 patients with TMB above 10 mutations/ Mb characterized as MSS and not having MMR or proofreading polymerases mutations. Mutations in genes encoding for proteins of the KRAS pathways were more frequent in MSS tumors with high TMB than in counterparts with low TMB. Moreover, genes involved in DNA damage response and in epigenetic regulations were more frequently mutated in MSS colorectal cancers with high TMB. CONCLUSION Alterations of the KRAS signal transduction pathways, DDR gene mutations and epigenetic modifier mutations may contribute to increase mutation burden in subsets of MSS colorectal cancers.
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Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, 750 Great Northern Road, Sault Ste Marie, Ontario, P6B 0A8, Canada; Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada.
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22
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Puzderova B, Belvoncikova P, Grossmannova K, Csaderova L, Labudova M, Fecikova S, Pastorek J, Barathova M. Propranolol, Promising Chemosensitizer and Candidate for the Combined Therapy through Disruption of Tumor Microenvironment Homeostasis by Decreasing the Level of Carbonic Anhydrase IX. Int J Mol Sci 2023; 24:11094. [PMID: 37446271 DOI: 10.3390/ijms241311094] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/30/2023] [Accepted: 07/01/2023] [Indexed: 07/15/2023] Open
Abstract
Resistance to chemotherapy represents a persisting medical problem, ranking among main causes of chemotherapy failure and cancer mortality. There is a possibility to utilize and repurpose already existing therapeutics which were not primarily intended for oncological treatment. Overactivation of adrenergic receptors and signaling dysregulation promotes tumor progression, metastatic potential, immune system evasion, tumor angiogenesis and drug resistance. The non-selective beta-blocker propranolol, approved in infantile haemangioma treatment, has a high potential for use in cancer therapy. We analyzed the effects of propranolol and 5-fluorouracil combination on sensitive and resistant cells derived from colorectal carcinoma in monolayers, single-component and co-culture spheroids and in vivo mouse models. Our results revealed that propranolol is able to exert its effect not only in chemosensitive colorectal cells, but also in 5-fluorouracil resistant cells. Propranolol disrupts the hypoxic adaptation machinery by inhibiting HIF1α, carbonic anhydrase IX, and activates apoptosis, which may be important in the management of chemo-resistant patients. We showed that propranolol slows down the growth of xenografts formed from colorectal cancer cells, even from cells already adapted to the β-blocker. We provide clear evidence that blockade of β-adrenergic receptors affects essential signaling pathways modulating tumor microenvironment and thus the response to anticancer therapy. Our findings indicate that propranolol could be repurposed to serve as chemosensitizer in combined therapy aimed at disrupting homeostasis of tumor microenvironment.
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Affiliation(s)
- Barbora Puzderova
- Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Petra Belvoncikova
- Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Katarina Grossmannova
- Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Lucia Csaderova
- Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Martina Labudova
- Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Silvia Fecikova
- National Institute of Lung Disaeses, Thorax Surgery and Tuberculosis, Vyšné Hágy 1, 059 84 Vysoké Tatry, Slovakia
| | | | - Monika Barathova
- Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
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Oura M, Oguro F, Agatsuma N, Imamaki H, Nishikawa Y. Fluoropyrimidine usage in cases with hyperammonemia: real-world data study using the Japanese Adverse Drug Event Report (JADER) database. Cancer Chemother Pharmacol 2023; 92:7-14. [PMID: 37204512 DOI: 10.1007/s00280-023-04542-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 05/09/2023] [Indexed: 05/20/2023]
Abstract
PURPOSE Fluoropyrimidines are anticancer drugs and can cause hyperammonemia both intravenously and orally. Renal dysfunction may interact with fluoropyrimidine to cause hyperammonemia. We performed quantitative analyses of hyperammonemia using a spontaneous report database to examine the frequency of intravenously and orally administered fluoropyrimidine, the reported frequency of fluoropyrimidine-related regimens, and fluoropyrimidine's interactions with chronic kidney disease (CKD). METHODS This study used data collected between April 2004 and March 2020 from the Japanese Adverse Drug Event Report database. The reporting odds ratio (ROR) of hyperammonemia was calculated for each fluoropyrimidine drug and was adjusted for age and sex. Heatmaps depicting the use of anticancer agents in patients with hyperammonemia were drawn. The interactions between CKD and the fluoropyrimidines were also calculated. These analyses were performed using multiple logistic regression. RESULTS Hyperammonemia was observed in 861 of the 641,736 adverse events reports. Fluorouracil was the most frequent drug associated with hyperammonemia (389 cases). The ROR of hyperammonemia was 32.5 (95% CI 28.3-37.2) for intravenously administered fluorouracil, 4.7 (95% CI 3.3-6.6) for orally administered capecitabine, 1.9 (95% CI 0.87-4.3) for tegafur/uracil, and 2.2 (95% CI 1.5-3.2) for orally administered tegafur/gimeracil/oteracil. Calcium levofolinate, oxaliplatin, bevacizumab, and irinotecan were the most frequently reported agents in cases of hyperammonemia with intravenously administered fluorouracil. The coefficient of the interaction term between CKD and fluoropyrimidines was 1.12 (95% CI 1.09-1.16). CONCLUSION Hyperammonemia cases were more likely to be reported with intravenous fluorouracil than orally administered fluoropyrimidines. Fluoropyrimidines might interact with CKD in hyperammonemia cases.
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Affiliation(s)
- Mitsuaki Oura
- Department of Internal Medicine, Takeda General Hospital, Fukushima, Japan
| | - Fumiya Oguro
- Department of Internal Medicine, Hirata Central Hospital, Fukushima, Japan
| | - Nobukazu Agatsuma
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hirotaka Imamaki
- Department of Nephrology, Hirakata Kohsai Hospital, Osaka, Japan
| | - Yoshitaka Nishikawa
- Department of Health Informatics, Kyoto University School of Public Health, Yoshidakonoecho, Sakyo-ku, Kyoto, 606-8501, Japan.
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24
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Baltussen JC, de Glas NA, Liefers GJ, Slingerland M, Speetjens FM, van den Bos F, Cloos-van Balen M, Verschoor AJ, Jochems A, Spierings LEAMM, Holterhues C, van Gerven LA, Mooijaart SP, Portielje JEA, Derks MGM. Time trends in treatment patterns and survival of older patients with synchronous metastatic colorectal cancer in the Netherlands: A population-based study. Int J Cancer 2023; 152:2043-2051. [PMID: 36620951 DOI: 10.1002/ijc.34422] [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: 10/20/2022] [Revised: 11/23/2022] [Accepted: 12/20/2022] [Indexed: 01/10/2023]
Abstract
New treatment strategies have improved survival of metastatic colorectal cancer in trials. However, it is not clear whether older patients benefit from these novel therapies, as they are often not included in pivotal trials. Therefore, we investigated treatment patterns and overall survival over time in older patients with metastatic colorectal cancer in a population-based study. We identified 22.192 Dutch patients aged ≥70 years diagnosed with synchronous metastatic colorectal cancer between 2005 and 2020 from the Netherlands Cancer Registry. Changes in treatment over time were assessed with logistic regression models. Survival was assessed by Cox proportional hazard ratios (HR). Results showed that chemotherapy use increased between 2005 and 2015, but declined from 2015 onwards, while more patients received best supportive care. Over time, fewer patients underwent primary tumor resection alone. Although survival of both metastatic colon and rectal cancer improved until 2014, survival of colon cancer decreased from 2014 onwards (HR 1.04, 95% confidence interval [CI] 1.01-1.05), which was seen in all age groups. Survival of metastatic rectal cancer patients remained unchanged from 2014 onwards (HR 1.00, 95% CI 0.98-1.03) in all age groups. In conclusion, treatment patterns of Dutch older patients with synchronous metastatic colorectal cancer rapidly changed from 2005 to 2020, with increasing percentages of patients receiving best supportive care. Survival of metastatic colon cancer decreased from 2014 onwards. The implementation of a colorectal cancer screening program and patient selection might explain why only a subset of older patients seem to benefit from the availability of novel treatment options.
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Affiliation(s)
- Joosje C Baltussen
- Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
| | - Nienke A de Glas
- Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
| | - Gerrit-Jan Liefers
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Marije Slingerland
- Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
| | - Frank M Speetjens
- Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
| | - Frederiek van den Bos
- Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Arjan J Verschoor
- Department of Medical Oncology, Reinier de Graaf Hospital, Delft, The Netherlands
| | - Anouk Jochems
- Department of Medical Oncology, Haaglanden Medical Center, The Hague, The Netherlands
| | | | - Cynthia Holterhues
- Department of Medical Oncology, Haga Hospital, The Hague, The Netherlands
| | - Leander A van Gerven
- Department of Internal Medicine, LangeLand Hospital, Zoetermeer, The Netherlands
| | - Simon P Mooijaart
- Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Marloes G M Derks
- Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
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Shi J, Sun Z, Gao Z, Huang D, Hong H, Gu J. Radioimmunotherapy in colorectal cancer treatment: present and future. Front Immunol 2023; 14:1105180. [PMID: 37234164 PMCID: PMC10206275 DOI: 10.3389/fimmu.2023.1105180] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 04/24/2023] [Indexed: 05/27/2023] Open
Abstract
Colorectal cancer (CRC) is a deadly form of cancer worldwide. Patients with locally advanced rectal cancer and metastatic CRC have a poor long-term prognosis, and rational and effective treatment remains a major challenge. Common treatments include multi-modal combinations of surgery, radiotherapy, and chemotherapy; however, recurrence and metastasis rates remain high. The combination of radiotherapy and immunotherapy (radioimmunotherapy [RIT]) may offer new solutions to this problem, but its prospects remain uncertain. This review aimed to summarize the current applications of radiotherapy and immunotherapy, elaborate on the underlying mechanisms, and systematically review the preliminary results of RIT-related clinical trials for CRC. Studies have identified several key predictors of RIT efficacy. Summarily, rational RIT regimens can improve the outcomes of some patients with CRC, but current study designs have limitations. Further studies on RIT should focus on including larger sample sizes and optimizing the combination therapy regimen based on underlying influencing factors.
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Affiliation(s)
- Jingyi Shi
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhuang Sun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhaoya Gao
- Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Dandan Huang
- Department of Oncology, Peking University Shougang Hospital, Beijing, China
| | - Haopeng Hong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jin Gu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
- Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China
- Peking Tsinghua Center for Life Science, Peking University International Cancer Center, Beijing, China
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26
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Jahedi M, Meshkini A. Tumor tropic delivery of FU.FA@NSs using mesenchymal stem cells for synergistic chemo-photodynamic therapy of colorectal cancer. Colloids Surf B Biointerfaces 2023; 226:113333. [PMID: 37141773 DOI: 10.1016/j.colsurfb.2023.113333] [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: 03/07/2023] [Revised: 04/19/2023] [Accepted: 04/29/2023] [Indexed: 05/06/2023]
Abstract
To overcome the limitations associated with the targeting abilities of nanotherapeutics and drug loading capacity of mesenchymal stem cells (MSCs), the present study relies on the combination of MSCs tumor tropism with the controlled release function of nano-based drug delivery platforms to achieve tumor-specific accumulation of chemotherapeutics with minimal off-target effects. 5-fluorouracil (5-FU)-containing ceria (CeNPs) coated calcium carbonate nanoparticles (CaNPs) were functionalized with folinic acid (FA) to develop drug-containing nanocomposites (Ca.FU.Ce.FA NCs). NCs were then conjugated with graphene oxide (GO) and decorated with silver nanoparticles (Ag°NPs) to form FU.FA@NS, a rationally designed drug delivery system with O2 generation capacity that alleviates tumor hypoxia for improved photodynamic therapy. Engineering of MSCs with FU.FA@NSs provided successful loading and long-term retention of therapeutics on the surface membrane with minimal changes to the functional properties of MSCs. Co-culturing of FU.FA@NS.MSCs with CT26 cells upon UVA exposure revealed enhanced apoptosis in tumor cells through ROS-mediated mitochondrial pathway. FU.FA@NSs released from MSCs were effectively taken up by CT26 cells via a clathrin-mediated endocytosis pathway and distributed their drug depots in a pH, H2O2, and UVA-stimulated fashion. Therefore, the cell-based biomimetic drug delivery platform formulated in the current study could be considered a promising strategy for targeted chemo-photodynamic therapy of colorectal cancer.
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Affiliation(s)
- Mehrnaz Jahedi
- Biochemical Research Center, Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, 9177948974 Mashhad, Iran
| | - Azadeh Meshkini
- Biochemical Research Center, Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, 9177948974 Mashhad, Iran; Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
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27
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Punt C, Heinemann V, Maughan T, Cremolini C, Van Cutsem E, McDermott R, Bodoky G, André T, Osterlund P, Teske A, Pfeiffer P. Fluoropyrimidine-induced hand-foot syndrome and cardiotoxicity: recommendations for the use of the oral fluoropyrimidine S-1 in metastatic colorectal cancer. ESMO Open 2023; 8:101199. [PMID: 37018874 PMCID: PMC10163153 DOI: 10.1016/j.esmoop.2023.101199] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 04/05/2023] Open
Abstract
BACKGROUND Fluoropyrimidines (FPs) are an essential part of the majority of systemic regimens in the treatment of metastatic colorectal cancer (CRC). The use of the oral FP S-1 has been approved by the European Medicines Agency as monotherapy or in combination with oxaliplatin or irinotecan, with or without bevacizumab, for the treatment of patients with metastatic CRC in whom it is not possible to continue treatment with another FP due to hand-foot syndrome (HFS) or cardiovascular toxicity (CVT). Subsequently, this indication has been included in the 2022 ESMO guidelines for metastatic CRC. Recommendations for use in daily practice are not available. PATIENTS AND METHODS Based on peer-reviewed published data on the use of S-1 in Western patients with metastatic CRC who switched from infusional 5-fluorouracil (5-FU) or capecitabine to S-1 for reasons of HFS or CVT, recommendations for its use were formulated by an international group of medical oncologists with expertise in the treatment of metastatic CRC and a cardio-oncologist. RESULTS In patients who experience pain and/or functional impairment due to HFS during treatment with capecitabine or infusional 5-FU, a switch to S-1 is recommended without prior dose reduction of capecitabine/5-FU. S-1 should preferably be initiated at full dose when HFS has decreased to grade ≤1. In patients with cardiac complaints, in whom an association with capecitabine or infusional 5-FU treatment cannot be excluded, capecitabine/5-FU should be discontinued and a switch to S-1 is recommended. CONCLUSIONS These recommendations should guide clinicians in daily practice in the treatment of patients with metastatic CRC with FP-containing regimens.
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28
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Dey A, Mitra A, Pathak S, Prasad S, Zhang AS, Zhang H, Sun XF, Banerjee A. Recent Advancements, Limitations, and Future Perspectives of the use of Personalized Medicine in Treatment of Colon Cancer. Technol Cancer Res Treat 2023; 22:15330338231178403. [PMID: 37248615 PMCID: PMC10240881 DOI: 10.1177/15330338231178403] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/18/2023] [Accepted: 03/13/2023] [Indexed: 08/29/2024] Open
Abstract
Due to the heterogeneity of colon cancer, surgery, chemotherapy, and radiation are ineffective in all cases. The genomic profile and biomarkers associated with the process are considered in personalized medicine, along with the patient's personal history. It is based on the response of the targeted therapies to specific genetic variations. The patient's genetic transcriptomic and epigenetic features are evaluated, and the best therapeutic approach and diagnostic testing are identified through personalized medicine. This review aims to summarize all the necessary, updated information on colon cancer related to personalized medicine. Personalized medicine is gaining prominence as generalized treatments are finding it challenging to contain colon cancer cases which currently rank fourth among global cancer incidence while being the fifth largest in total death cases worldwide. In personalized therapy, patients are grouped into specific categories, and the best therapeutic approach is chosen based on evaluating their molecular features. Various personalized strategies are currently being explored in the treatment of colon cancer involving immunotherapy, phytochemicals, and other biomarker-specific targeted therapies. However, significant challenges must be overcome to integrate personalized medicine into healthcare systems completely. We look at the various signaling pathways and genetic and epigenetic alterations associated with colon cancer to understand and identify biomarkers useful in targeted therapy. The current personalized therapies available in colon cancer treatment and the strategies being explored to improve the existing methods are discussed. This review highlights the advantages and limitations of personalized medicine in colon cancer therapy. The current scenario of personalized medicine in developed countries and the challenges faced in middle- and low-income countries are also summarized. Finally, we discuss the future perspectives of personalized medicine in colon cancer and how it could be integrated into the healthcare systems.
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Affiliation(s)
- Amit Dey
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Chennai, India
| | - Abhijit Mitra
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Chennai, India
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Chennai, India
| | - Suhanya Prasad
- Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Bialystok, Białystok, Poland
| | | | - Hong Zhang
- School of Medicine, Department of Medical Sciences, Orebro University, Örebro, Sweden
| | - Xiao-Feng Sun
- Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Antara Banerjee
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Chennai, India
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29
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Ito K, Osakabe M, Sugimoto R, Yamada S, Sato A, Uesugi N, Yanagawa N, Suzuki H, Sugai T. Differential Expression in the Tumor Microenvironment of mRNAs Closely Associated with Colorectal Cancer Metastasis. Ann Surg Oncol 2023; 30:1255-1266. [PMID: 36222933 PMCID: PMC9807483 DOI: 10.1245/s10434-022-12574-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 08/28/2022] [Indexed: 01/07/2023]
Abstract
BACKGROUND Metastasis of colorectal cancer (CRC) is a major cause of CRC-related mortality. However, the detailed molecular mechanism of CRC metastasis remains unknown. A recent study showed that the tumor microenvironment, which includes cancer cells and the surrounding stromal cells, plays a major role in tumor invasion and metastasis. Identification of altered messenger RNA (mRNA) expression in the tumor microenvironment is essential to elucidation of the mechanisms responsible for tumor progression. This study investigated the mRNA expression of genes closely associated with metastatic CRC compared with non-metastatic CRC. METHODS The samples examined were divided into cancer tissue and isolated cancer stromal tissue. The study examined altered mRNA expression in the cancer tissues using The Cancer Genome Atlas (TCGA) (377cases) and in 17 stromal tissues obtained from our laboratory via stromal isolation using an array-based analysis. In addition, 259 patients with CRC were enrolled to identify the association of the candidate markers identified with the prognosis of patients with stage 2 or 3 CRC. The study examined the enriched pathways identified by gene set enrichment analysis (GSEA) based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) module in both the TCGA dataset and isolated stromal tissue. RESULTS As a result, whereas tenascin-C, secreted phosphoprotein 1 and laminin were expressed in metastatic CRC cells, olfactory receptors (ORs) 11H1 and OR11H4 were expressed in stromal tissue cells isolated from metastatic CRC cases. Finally, upregulated expression of tenascin-C and OR11H4 was correlated with the outcome for CRC patients. CONCLUSION The authors suggest that upregulated expression levels of tenascin-C and OR11H1 play an important role in CRC progression.
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Affiliation(s)
- Kazuhiro Ito
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun’yahabachou, Japan
| | - Mitsumasa Osakabe
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun’yahabachou, Japan
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun’yahabachou, Japan
| | - Shun Yamada
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun’yahabachou, Japan
| | - Ayaka Sato
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun’yahabachou, Japan
| | - Noriyuki Uesugi
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun’yahabachou, Japan
| | - Naoki Yanagawa
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun’yahabachou, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun’yahabachou, Japan
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30
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Boku S, Satake H, Ohta T, Mitani S, Kawakami K, Suzuki Y, Matsumoto T, Terazawa T, Yamazaki E, Hasegawa H, Ikoma T, Uemura M, Yamaguchi T, Naito A, Ishizuka Y, Kurokawa Y, Sakai D, Kawakami H, Shimokawa T, Tsujinaka T, Kato T, Satoh T, Kagawa Y. TRESBIEN (OGSG 2101): encorafenib, binimetinib and cetuximab for early recurrent stage II/III BRAF V600E-mutated colorectal cancer. Future Oncol 2022; 18:4153-4160. [PMID: 36475784 DOI: 10.2217/fon-2022-0949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 11/21/2022] [Indexed: 12/13/2022] Open
Abstract
The BRAF V600E mutation accounts for approximately 5% of colorectal cancer (CRC) cases and is an extremely poor prognostic factor. However, there are no clear recommendations regarding first-line therapy for patients with early recurrent BRAF V600E-mutated CRC, during or after adjuvant chemotherapy. Recently, a novel combination of encorafenib, binimetinib and cetuximab, showed a higher response rate than standard chemotherapy in patients with BRAF V600E-mutated CRC. Here we describe our plan for the TRESBIEN study (OGSG 2101), which is an open-label, multicenter, single-arm, phase II study designed to evaluate whether encorafenib, binimetinib and cetuximab are effective for patients with early recurrent BRAF V600E-mutated colorectal cancer, during or after adjuvant chemotherapy. The planned number of subjects is 25.
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Affiliation(s)
- Shogen Boku
- Cancer Treatment Center, Kansai Medical University Hospital, Hirakata, 573-1191, Japan
| | - Hironaga Satake
- Department of Medical Oncology, Kochi Medical School, Nankoku, 783-8505, Japan
| | - Takashi Ohta
- Department of Clinical Oncology, Kansai Rosai Hospital, Amagasaki, 660-8511, Japan
| | - Seiichiro Mitani
- Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka-Sayama, 589-8511, Japan
| | - Kentaro Kawakami
- Department of Medical Oncology, Keiyukai Sapporo Hospital, Sapporo, 003-0027, Japan
| | - Yozo Suzuki
- Department of Surgery, Toyonaka Municipal Hospital, Toyonaka, 560-8565, Japan
| | - Toshihiko Matsumoto
- Cancer Treatment Center, Kansai Medical University Hospital, Hirakata, 573-1191, Japan
| | - Tetsuji Terazawa
- Cancer Chemotherapy Center, Osaka Medical & Pharmaceutical University Hospital, Takatsuki, 569-8686, Japan
| | - Eiki Yamazaki
- Cancer Chemotherapy Center, Osaka Medical & Pharmaceutical University Hospital, Takatsuki, 569-8686, Japan
| | - Hiroko Hasegawa
- Department of Gastroenterology & Hepatology, National Hospital Organization, Osaka National Hospital, Osaka, 578-8588, Japan
| | - Tatsuki Ikoma
- Cancer Treatment Center, Kansai Medical University Hospital, Hirakata, 573-1191, Japan
| | - Mamoru Uemura
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan
| | - Toshifumi Yamaguchi
- Cancer Chemotherapy Center, Osaka Medical & Pharmaceutical University Hospital, Takatsuki, 569-8686, Japan
| | - Atsushi Naito
- Department of Surgery, Osaka Police Hospital, Osaka, 543-8502, Japan
| | - Yasunobu Ishizuka
- Department of Medical Oncology, Osaka International Cancer Institute, Osaka, 541-8567, Japan
| | - Yukinori Kurokawa
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan
| | - Daisuke Sakai
- Center for Cancer Genomics & Personalized Medicine, Osaka University Hospital, Suita, 565-0871, Japan
| | - Hisato Kawakami
- Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka-Sayama, 589-8511, Japan
| | - Toshio Shimokawa
- Clinical Study Support Center, Wakayama Medical University Hospital, Wakayama, 641-8509, Japan
| | | | - Takeshi Kato
- Department of Colorectal Surgery, National Hospital Organization, Osaka National Hospital, Osaka, 578-8588, Japan
| | - Taroh Satoh
- Palliative & Supportive Care Center, Osaka University Hospital, Suita, 565-0871, Japan
| | - Yoshinori Kagawa
- Department of Colorectal Surgery, Osaka General Medical Center, Osaka, 558-8588, Japan
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31
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Long S, Wang J, Weng F, Pei Z, Zhou S, Sun G, Xiang D. ECM1 regulates the resistance of colorectal cancer to 5-FU treatment by modulating apoptotic cell death and epithelial-mesenchymal transition induction. Front Pharmacol 2022; 13:1005915. [PMID: 36408224 PMCID: PMC9666402 DOI: 10.3389/fphar.2022.1005915] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/19/2022] [Indexed: 01/25/2023] Open
Abstract
5-Fluorouracil (5-FU) chemoresistance is a persistent impediment to the efficient treatment of many types of cancer, yet the molecular mechanisms underlying such resistance remain incompletely understood. Here we found CRC patients resistant to 5-FU treatment exhibited increased extracellular matrix protein 1 (ECM1) expression compared to CRC patients sensitive to this chemotherapeutic agent, and higher levels of ECM1 expression were correlated significantly with shorter overall survival and disease-free survival. 5-FU resistant HCT15 (HCT15/FU) cells expressed significantly higher levels of ECM1 relative to parental HCT15 cells. Changes in ECM1 expression altered the ability of both parental and HCT15/FU cells to tolerate the medication in vitro and in vivo via processes associated with apoptosis and EMT induction. From a mechanistic perspective, knocking down and overexpressing ECM1 in HCT15/FU and HCT15 cell lines inhibited and activated PI3K/AKT/GSK3β signaling, respectively. Accordingly, 5-FU-induced apoptotic activity and EMT phenotype changes were affected by treatment with PI3K/AKT agonists and inhibitors. Together, these data support a model wherein ECM1 regulates CRC resistance to 5-FU via PI3K/AKT/GSK3β pathway-mediated modulation of apoptotic resistance and EMT induction, highlighting ECM1 as a promising target for therapeutic intervention for efforts aimed at overcoming chemoresistance in CRC patients.
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Affiliation(s)
- Sirui Long
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China,Department of Oncology, Jiangjin Central Hospital of Chongqing, Chongqing, China
| | - Jie Wang
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China,Department of Oncology, Jiangjin Central Hospital of Chongqing, Chongqing, China
| | - Fanbin Weng
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China,Department of Oncology, Jiangjin Central Hospital of Chongqing, Chongqing, China
| | - Zhigang Pei
- Department of Pathology, Chongqing University Jiangjin Hospital, Chongqing, China,Department of Pathology, Jiangjin Central Hospital of Chongqing, Chongqing, China
| | - Shixian Zhou
- Department of Pathology, Chongqing University Jiangjin Hospital, Chongqing, China,Department of Pathology, Jiangjin Central Hospital of Chongqing, Chongqing, China
| | - Guiyin Sun
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China,Department of Oncology, Jiangjin Central Hospital of Chongqing, Chongqing, China,*Correspondence: Guiyin Sun, ; Debing Xiang,
| | - Debing Xiang
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China,Department of Oncology, Jiangjin Central Hospital of Chongqing, Chongqing, China,*Correspondence: Guiyin Sun, ; Debing Xiang,
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32
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Russo V, Lallo E, Munnia A, Spedicato M, Messerini L, D’Aurizio R, Ceroni EG, Brunelli G, Galvano A, Russo A, Landini I, Nobili S, Ceppi M, Bruzzone M, Cianchi F, Staderini F, Roselli M, Riondino S, Ferroni P, Guadagni F, Mini E, Peluso M. Artificial Intelligence Predictive Models of Response to Cytotoxic Chemotherapy Alone or Combined to Targeted Therapy for Metastatic Colorectal Cancer Patients: A Systematic Review and Meta-Analysis. Cancers (Basel) 2022; 14:4012. [PMID: 36011003 PMCID: PMC9406544 DOI: 10.3390/cancers14164012] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/26/2022] [Accepted: 08/12/2022] [Indexed: 12/24/2022] Open
Abstract
Tailored treatments for metastatic colorectal cancer (mCRC) have not yet completely evolved due to the variety in response to drugs. Therefore, artificial intelligence has been recently used to develop prognostic and predictive models of treatment response (either activity/efficacy or toxicity) to aid in clinical decision making. In this systematic review, we have examined the ability of learning methods to predict response to chemotherapy alone or combined with targeted therapy in mCRC patients by targeting specific narrative publications in Medline up to April 2022 to identify appropriate original scientific articles. After the literature search, 26 original articles met inclusion and exclusion criteria and were included in the study. Our results show that all investigations conducted on this field have provided generally promising results in predicting the response to therapy or toxic side-effects. By a meta-analytic approach we found that the overall weighted means of the area under the receiver operating characteristic (ROC) curve (AUC) were 0.90, 95% C.I. 0.80-0.95 and 0.83, 95% C.I. 0.74-0.89 in training and validation sets, respectively, indicating a good classification performance in discriminating response vs. non-response. The calculation of overall HR indicates that learning models have strong ability to predict improved survival. Lastly, the delta-radiomics and the 74 gene signatures were able to discriminate response vs. non-response by correctly identifying up to 99% of mCRC patients who were responders and up to 100% of patients who were non-responders. Specifically, when we evaluated the predictive models with tests reaching 80% sensitivity (SE) and 90% specificity (SP), the delta radiomics showed an SE of 99% and an SP of 94% in the training set and an SE of 85% and SP of 92 in the test set, whereas for the 74 gene signatures the SE was 97.6% and the SP 100% in the training set.
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Affiliation(s)
- Valentina Russo
- Research and Development Branch, Regional Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy
| | - Eleonora Lallo
- Research and Development Branch, Regional Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy
| | - Armelle Munnia
- Research and Development Branch, Regional Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy
| | - Miriana Spedicato
- Research and Development Branch, Regional Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy
| | - Luca Messerini
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Romina D’Aurizio
- Institute of Informatics and Telematics, National Research Council, 56124 Pisa, Italy
| | - Elia Giuseppe Ceroni
- Institute of Informatics and Telematics, National Research Council, 56124 Pisa, Italy
| | - Giulia Brunelli
- Institute of Informatics and Telematics, National Research Council, 56124 Pisa, Italy
| | - Antonio Galvano
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Antonio Russo
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Ida Landini
- Department of Health Sciences, University of Florence, 50139 Florence, Italy
| | - Stefania Nobili
- Department of Neurosciences, Imaging and Clinical Sciences, “G. D’Annunzio” Chieti-Pescara, 66100 Chieti, Italy
| | - Marcello Ceppi
- Clinical Epidemiology Unit, IRCCS-Ospedale Policlinico San Martino, 16131 Genova, Italy
| | - Marco Bruzzone
- Clinical Epidemiology Unit, IRCCS-Ospedale Policlinico San Martino, 16131 Genova, Italy
| | - Fabio Cianchi
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Fabio Staderini
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Mario Roselli
- Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy
| | - Silvia Riondino
- Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy
| | - Patrizia Ferroni
- BioBIM (InterInstitutional Multidisciplinary Biobank), IRCCS San Raffaele Roma, 00166 Rome, Italy
- Department of Human Sciences & Quality of Life Promotion, San Raffaele Roma Open University, 00166 Rome, Italy
| | - Fiorella Guadagni
- BioBIM (InterInstitutional Multidisciplinary Biobank), IRCCS San Raffaele Roma, 00166 Rome, Italy
- Department of Human Sciences & Quality of Life Promotion, San Raffaele Roma Open University, 00166 Rome, Italy
| | - Enrico Mini
- Department of Health Sciences, University of Florence, 50139 Florence, Italy
| | - Marco Peluso
- Research and Development Branch, Regional Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy
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Wu CWK, Reid M, Leedham S, Lui RN. The emerging era of personalized medicine in advanced colorectal cancer. J Gastroenterol Hepatol 2022; 37:1411-1425. [PMID: 35815339 PMCID: PMC7617119 DOI: 10.1111/jgh.15937] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 12/09/2022]
Abstract
Colorectal cancer (CRC) is a genetically heterogeneous disease with its pathogenesis often driven by varying genetic or epigenetic alterations. This has led to a substantial number of patients developing chemoresistance and treatment failure, resulting in a high mortality rate for advanced disease. Deep molecular analysis has allowed for the discovery of key intestinal signaling pathways which impacts colonic epithelial cell fate, and the integral role of the tumor microenvironment on cancer growth and dissemination. Through transitioning pre-clinical knowledge in research into clinical practice, many potential druggable targets within these pathways have been discovered in the hopes of overcoming the roadblocks encountered by conventional therapies. A personalized approach tailoring treatment according to the histopathological and molecular features of individual tumors can hopefully translate to better patient outcomes, and reduce the rate of recurrence in patients with advanced CRC. Herein, the latest understanding on the molecular science behind CRC tumorigenesis, and the potential treatment targets currently at the forefront of research are summarized.
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Affiliation(s)
- Claudia WK Wu
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China
| | - Madeleine Reid
- Translational Gastroenterology Unit, John Radcliffe hospital, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Simon Leedham
- Translational Gastroenterology Unit, John Radcliffe hospital, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Rashid N Lui
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China
- Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China
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Cho YB, Kim JW, Heo K, Kim HJ, Yun S, Lee HS, Shin HG, Shim H, Yu H, Kim YH, Lee S. An internalizing antibody targeting of cell surface GRP94 effectively suppresses tumor angiogenesis of colorectal cancer. Biomed Pharmacother 2022; 150:113051. [PMID: 35658213 DOI: 10.1016/j.biopha.2022.113051] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/26/2022] [Accepted: 04/26/2022] [Indexed: 11/16/2022] Open
Abstract
Colorectal cancer (CRC) is one of the life-threatening malignancies worldwide. Thus, novel potential therapeutic targets and therapeutics for the treatment of CRC need to be identified to improve the clinical outcomes of patients with CRC. In this study, we found that glucose-regulated protein 94 (GRP94) is overexpressed in CRC tissues, and its high expression is correlated with increased microvessel density. Next, through phage display technology and consecutive in vitro functional isolations, we generated a novel human monoclonal antibody that specifically targets cell surface GRP94 and shows superior internalizing activity comparable to trastuzumab. We found that this antibody specifically inhibits endothelial cell tube formation and simultaneously promotes the downregulation of GRP94 expression on the endothelial cell surface. Finally, we demonstrated that this antibody effectively suppresses tumor growth and angiogenesis of HCT116 human CRC cells without causing severe toxicity in vivo. Collectively, these findings suggest that cell surface GRP94 is a novel potential anti-angiogenic target in CRC and that antibody targeting of GRP94 on the endothelial cell surface is an effective strategy to suppress CRC tumor angiogenesis.
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Affiliation(s)
- Yea Bin Cho
- Department of Chemistry, Kookmin University, Seoul 02707, Republic of Korea
| | - Ji Woong Kim
- Department of Chemistry, Kookmin University, Seoul 02707, Republic of Korea
| | - Kyun Heo
- Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Republic of Korea; Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 02707, Republic of Korea; Antibody Research Institute, Kookmin University, Seoul 02707, Republic of Korea
| | - Hyun Jung Kim
- Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Republic of Korea; Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 02707, Republic of Korea
| | - Sumi Yun
- Samkwang Medical Laboratories, Department of Diagnostic Pathology, Seoul 06742, Republic of Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Ha Gyeong Shin
- Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Republic of Korea
| | - Hyunbo Shim
- Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Hanjin Yu
- HauulBio, Chuncheon, Gangwon 24398, Republic of Korea
| | - Yun-Hee Kim
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Republic of Korea; Division of Convergence Technology, Research Institute of National Cancer Center, Goyang 10408, Republic of Korea
| | - Sukmook Lee
- Department of Chemistry, Kookmin University, Seoul 02707, Republic of Korea; Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Republic of Korea; Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 02707, Republic of Korea; Antibody Research Institute, Kookmin University, Seoul 02707, Republic of Korea.
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Cruz-Nova P, Ancira-Cortez A, Ferro-Flores G, Ocampo-García B, Gibbens-Bandala B. Controlled-Release Nanosystems with a Dual Function of Targeted Therapy and Radiotherapy in Colorectal Cancer. Pharmaceutics 2022; 14:pharmaceutics14051095. [PMID: 35631681 PMCID: PMC9145578 DOI: 10.3390/pharmaceutics14051095] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 05/13/2022] [Accepted: 05/15/2022] [Indexed: 12/14/2022] Open
Abstract
Nanoparticles are excellent platforms for several biomedical applications, including cancer treatment. They can incorporate different molecules to produce combinations of chemotherapeutic agents, radionuclides, and targeting molecules to improve the therapeutic strategies against cancer. These specific nanosystems are designed to have minimal side effects on healthy cells and better treatment efficacy against cancer cells when compared to chemotherapeutics, external irradiation, or targeted radiotherapy alone. In colorectal cancer, some metal and polymeric nanoparticle platforms have been used to potentialize external radiation therapy and targeted drug delivery. Polymeric nanoparticles, liposomes, albumin-based nanoparticles, etc., conjugated with PEG and/or HLA, can be excellent platforms to increase blood circulation time and decrease side effects, in addition to the combination of chemo/radiotherapy, which increases therapeutic efficacy. Additionally, radiolabeled nanoparticles have been conjugated to target specific tissues and are mainly used as agents for diagnosis, drug/gene delivery systems, or plasmonic photothermal therapy enhancers. This review aims to analyze how nanosystems are shaping combinatorial therapy and evaluate their status in the treatment of colorectal cancer.
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Alawabdeh T, Ellati RT, Amarin R, Masoud W, Abuhijlih R. Acute Arterial Thrombosis in a Colon Cancer patient after Administration of Oxaliplatin with Capecitabine Chemotherapy “case report”. CURRENT PROBLEMS IN CANCER: CASE REPORTS 2022. [DOI: 10.1016/j.cpccr.2022.100166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Shi HY, Chen YC, Huang CW, Li CC, Su WC, Chang TK, Chen PJ, Yin TC, Tsai HL, Wang JY. Effectiveness and Cost-Utility Analysis of Different Doses of Irinotecan Plus Bevacizumab in Patients With Metastatic Colorectal Cancer: A Long-Term and Prospective Cohort Study. Front Oncol 2022; 12:756078. [PMID: 35359363 PMCID: PMC8964058 DOI: 10.3389/fonc.2022.756078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 02/22/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE Patients with metastatic colorectal cancer (mCRC) had oncological benefits with irinotecan dose escalation of FOLFIRI regimen combined with bevacizumab according to UGT1A1 genotypes in our previous study. In the current study, we performed a quality of life (QOL) outcome evaluation and cost-utility analysis of different irinotecan dose regimens in patients with mCRC. MATERIALS AND METHODS With inverse probability-of-treatment weighting (IPTW) matching on all covariates, 75 patients with dose escalation of irinotecan (study group) and 121 patients with the recommended dose of irinotecan (control group) were recruited between October 2015 and December 2019. The QOL outcome measures were Functional Assessment of Cancer Therapy-Colorectal, Beck Anxiety Inventory, Beck Depression Inventory, and SF-36; cost-utility outcome measures were medical direct costs, quality-adjusted life-years (QALYs), and incremental cost-utility ratios (ICURs). RESULTS All mCRC patients exhibited a significant decrease in both emotional wellbeing and depression from pretherapeutic period to posttherapeutic 6th month (P < 0.05); however, from the posttherapeutic 1st year to the 2nd year, improvement in most QOL measures was significantly better in the study group than in the control group (P < 0.05). Over a 2-year time period, the study group had higher total medical direct costs than the control group (US$ 54,742 ± 14,013 vs. US$ 54,608 ± 9,673) and higher average QALYs gained (1.88 vs. 1.65), with an ICUR of US$ 583 per QALY gained. CONCLUSION For patients with mCRC, irinotecan dose escalation appeared cost-effective with considerable QOL improvements during the study period. Further randomized, multi-institutional controlled trials are warranted to corroborate these results.
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Affiliation(s)
- Hon-Yi Shi
- Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Business Management, National Sun Yat-sen University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Yen-Cheng Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Wen Huang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Chun Li
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wei-Chih Su
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tsung-Kun Chang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Jung Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tzu-Chieh Yin
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Kaohsiung Municipal Tatung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsiang-Lin Tsai
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jaw-Yuan Wang
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Pingtung Hospital, Ministry of Health and Welfare, Pingtung, Taiwan
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38
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Zhou Y, Zhang Q, Wang M, Huang C, Yao X. Effective Delivery of siRNA-Loaded Nanoparticles for Overcoming Oxaliplatin Resistance in Colorectal Cancer. Front Oncol 2022; 12:827891. [PMID: 35265524 PMCID: PMC8898837 DOI: 10.3389/fonc.2022.827891] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 01/20/2022] [Indexed: 01/05/2023] Open
Abstract
Chemotherapy resistance represents a formidable obstacle in advanced or metastatic colorectal cancer (CRC) patients. It is reported that ATPase copper transporting alpha (ATP7A) plays an important role in chemotherapy resistance in CRC. Here, we identified ATP7A as a potentially key gene of OXA resistance in CRC. The patients with higher expression of ATP7A tended to have platinum drug resistance. While the lower expression of ATP7A by siRNA knockdown resulted in enhancement of OXA sensitivity and increased OXA-induced apoptosis. Further, we demonstrated a novel and safe strategy to increase CRC chemosensitivity by delivering siRNA into tumor cells via a novel nanoparticle, DAN. In summary, our study provided a novel nanocarrier-based delivery of ATP7A to interfere in a key gene of chemo-resistance in CRC, which may be a novel therapeutic strategy to overcome chemotherapy resistance in CRC.
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Affiliation(s)
- Yue Zhou
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Gastrointestinal Surgery, Ganzhou Municipal Hospital, Ganzhou, China.,Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China
| | - Qing Zhang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Gastrointestinal Surgery, Ganzhou Municipal Hospital, Ganzhou, China.,Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.,Department of Gastrointestinal and Anorectal Surgery, The First People's Hospital of Zhaoqing, Zhaoqing, China
| | - Minjia Wang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Gastrointestinal Surgery, Ganzhou Municipal Hospital, Ganzhou, China.,Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China
| | - Chengzhi Huang
- Department of Gastrointestinal Surgery, Ganzhou Municipal Hospital, Ganzhou, China.,Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China
| | - Xueqing Yao
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Gastrointestinal Surgery, Ganzhou Municipal Hospital, Ganzhou, China.,Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China
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Hou Z, Liu J, Jin Z, Qiu G, Xie Q, Mi S, Huang J. Use of chemotherapy to treat hepatocellular carcinoma. Biosci Trends 2022; 16:31-45. [PMID: 35173139 DOI: 10.5582/bst.2022.01044] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatic malignancies remain a global challenge. Hepatocellular carcinoma (HCC) accounts for around 90% of patients with liver cancer and is the sixth most common neoplasm worldwide and the fourth leading cause of cancer-related death. However, the long-term prognosis for HCC remains far from satisfactory, with a late diagnosis and limited treatment. DOX has served as conventional chemotherapy with the longest history of use. Although conventional chemotherapy is being challenged by molecular therapy and immune therapy, there is renewed optimism and interest in both systematic and locoregional therapy. Combined chemotherapy is widely used in clinical practice. In specific terms, FOLFOX can serve as a first-line (category 2B) option as recommended by the 2021 NCCN guidelines, while the efficacy of LTLD plus RFA has been confirmed in the phase III HEAT study. These approaches have challenged the dominant status of molecular therapy in terms of health economics and they have potential benefits in Asia, where HBV-related hepatocellular carcinoma is prevalent. Moreover, locoregional chemotherapy can be achieved with TACE and HAIC (possibly involving FOLFOX, DOX, mitomycin C, cisplatin, epirubicin, etc.). TACE was officially recommended by the 2021 NCCN guidelines for patients with Child-Pugh class B liver disease. In addition, HAIC has demonstrated a potential advantage in preliminary clinical practice, although it hasn't been included in any guidelines. Hence, this review summarizes large-scale trials and studies examining the development and innovative use of chemotherapeutic agents. Mounting clinical evidence warrants an exploration of the efficacy of chemotherapy.
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Affiliation(s)
- Ziqi Hou
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Liu
- Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhaoxing Jin
- Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Guoteng Qiu
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qingyun Xie
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Shizheng Mi
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jiwei Huang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
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40
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Rumpold H, Hackl M, Petzer A, Wolf D. Improvement in colorectal cancer outcomes over time is limited to patients with left-sided disease. J Cancer Res Clin Oncol 2022; 148:3007-3014. [PMID: 34977964 DOI: 10.1007/s00432-021-03868-0] [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: 10/08/2021] [Accepted: 11/21/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE Incidence and mortality of colorectal cancer (CRC) declined over the last decades. However, survival depends on the primary tumor location. It is unknown if all progress in outcomes vary depending on left-sided (LCRC) versus right-sided (RCC) colorectal cancer. We compare incidence and mortality rates over time according to the primary tumor location. METHODS Data from the Austrian National Cancer Registry spanning from 1983 to 2018 were used to calculate annual incidence and mortality rates and survival stratified by primary tumor localization and stage. Joinpoint regression with linear regression models were used on different subgroups to identify significant changes of incidence- and mortality slopes. RESULTS A total of 168,260 (incidence dataset) and 87,355 cases (mortality dataset) were identified. Survival of disseminated RCC was worse compared to LCRC (HR 1.14; CI 1.106-1.169). Total and LCRC incidence and mortality rates declined steadily over time, whereas the rates of RCC did not. Incidence of disseminated RCC declined significantly less (slope - 0.07; CI - 0.086; - 0.055) than in LCRC (slope - 0.159; CI - 0.183; - 0.136); mortality rate of RCC was unchanged over time. Incidence and mortality of localized RCC remained unchanged over time, whereas both rates declined independently of stage in LCRC. CONCLUSION Colorectal cancer outcomes during the last 35 years have preferentially improved in LCRC but not in RCC, indicating that the progress made is limited to LCRC. It is necessary to define RCC as a distinct form of CRC and to focus on specific strategies for its early detection and treatment.
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Affiliation(s)
- Holger Rumpold
- Gastrointestinal Cancer Center, Ordensklinikum Linz, Seilerstaette 4, 4010, Linz, Austria. .,Medical Faculty, Johannes Kepler University, Linz, Austria.
| | - M Hackl
- National Cancer Registry, Statistics Austria, Vienna, Austria
| | - A Petzer
- Department of Medical Oncology and Hematology, Ordensklinikum Linz, Linz, Austria
| | - D Wolf
- Internal Medicine 5, Department of Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria
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Qi X, Yan D, Zuo J, Wang R, Chen J. Development of a novel chemokine signaling-based multigene signature to predict prognosis and therapeutic response in colorectal cancer. J Zhejiang Univ Sci B 2021; 22:1053-1059. [PMID: 34904417 DOI: 10.1631/jzus.b2100412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Colorectal cancer (CRC) is the most lethal gastrointestinal cancer in both males and females worldwide (Sung et al., 2021). Because of the high heterogeneity of tumors, robust prognostic biomarkers are urgently needed in CRC management (Koncina et al., 2020). Chemokine signaling is a well-known pivotal player in immunity, inflammation, and cancer metastasis (Lacalle et al., 2017; Poeta et al., 2019; Do et al., 2020), and multiple genes involved in chemokine signaling have been demonstrated as potential prognostic biomarkers for CRC (Cabrero-De Las Heras and Martínez-Balibrea, 2018; Ottaiano et al., 2020; Yu et al., 2020). Therefore, the aim of our study was to develop a chemokine signaling-based multigene signature (CSbMgSig) that could effectively predict overall survival (OS) and therapeutic response for patients with CRC.
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Affiliation(s)
- Xin Qi
- School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou 215011, China.
| | - Donghui Yan
- School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou 215011, China
| | - Jiachen Zuo
- School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou 215011, China
| | - Rui Wang
- School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou 215011, China
| | - Jiajia Chen
- School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou 215011, China
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Minotti G, Camilli M. Risk of Myocardial Infarction in Patients Treated With 5-Fluorouracil: Balancing the Evidence With Black Boxes. JACC CardioOncol 2021; 3:734-736. [PMID: 34988483 PMCID: PMC8702785 DOI: 10.1016/j.jaccao.2021.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Affiliation(s)
- Giorgio Minotti
- Department of Medicine, University Campus Bio-Medico, Rome, Italy
| | - Massimiliano Camilli
- Department of Medicine, Cardiovascular and Thoracic Sciences, Catholic University of the Sacred Heart, Rome, Italy
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