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1
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Fadaly WAA, Nemr MTM, Abd El-Hameed AM, Mohamed FEA, Zidan TH. Design and Synthesis of New pyrazole Hybrids Linked to Oxime and Nitrate Moieties as COX-2, EGFR L858R/T790M Inhibitors and Nitric Oxide Donors with dual Anti-inflammatory/Anti-proliferative Activities. Bioorg Chem 2025; 161:108563. [PMID: 40349531 DOI: 10.1016/j.bioorg.2025.108563] [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: 01/08/2025] [Revised: 05/01/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
Two new series of pyrazole derivatives 14a-l and 17a-c with oxime/nitrate moieties as EGFRWT, mutant (EGFRL858R/T790M) and COX-2 inhibitors were synthesized and evaluated for anti-proliferative and anti-inflammatory activities. Compounds 14c, 14e, 14 g, 14i-l, 17b and 17c exhibited COX-2 selectivity in the range of (S.I. = 17-42) when compared to celecoxib (S.I. = 20.43). Concerning anti-neoplastic activity, screening was carried out against 60 human cancer cell lines by (NCI); Nine compounds (14c, 14e, 14 g, 14i-l, 17b and 17c) showed excellent inhibitory activity against all cancer cell lines especially non-small cell lung cancer (NSCLC). Further cytotoxicity testing of compounds 14c, 14e, 14 g, 14i-l, 17b and 17c was conducted on established EGFRT790M/L858R-resistant NSCLC (H1975), all tested compounds except 14 l exhibited potent activity (IC50 = 3.02-27.32 μM) which is higher than that of osimertinib (IC50 = 37.29 μM). It was noted that compound 17c, showed cell cycle arrest at G0/G1 phase of NSCLC (H1975) cells. In addition, compounds 14c, 14e, 14 g, 14i-l, 17b and 17c induced improved selective inhibitory activity against double mutant EGFRL858R/T790M tyrosine kinases with IC50 in the range of (0.031-0.076 μM, with selectivity index range S.I. of 2.5-14.58) which was comparable to that of osimertinib (IC50 = 0.037 μM, with S.I. of 1.89). The most potent anti-cancer compounds 14c, 14e, 14 g, 14i-l, 17b and 17c released NO in a slow rate of (1.45-3.37 %). Finally, applying covalent docking, we identified the covalent binding of 14 g, 14 k, and 17c with Cys797, providing insights into their potential as irreversible inhibitors targeting EGFRL858R/T790M protein.
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Affiliation(s)
- Wael A A Fadaly
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
| | - Mohamed T M Nemr
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini Street, 11562 Cairo, Egypt.
| | - Abeer M Abd El-Hameed
- Chemistry Department, Faculty of Science, Taibah University, P.O. BOX 30002, Al-Madinah, Al-Munawarah 14177, Saudi Arabia
| | - Fatma E A Mohamed
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
| | - Taha H Zidan
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
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2
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Liu D, Gong J, Zhang J, Shu Y, Wu H, Liu T, Xu Y, Zhang L, Li M, Hu X, Shen L. A phase I dose-escalation and expansion study of RMX1002, a selective E-type prostanoid receptor 4 antagonist, as monotherapy and in combination with anti-PD-1 antibody in advanced solid tumors. Invest New Drugs 2025; 43:250-261. [PMID: 39976872 PMCID: PMC12048420 DOI: 10.1007/s10637-025-01512-z] [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: 11/18/2024] [Accepted: 01/28/2025] [Indexed: 05/03/2025]
Abstract
RMX1002 (grapiprant) is a selective E-type prostanoid receptor 4 (EP4) antagonist and a promising candidate for cancer therapy, potentially enhancing anti-tumor immune responses. This study aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of RMX1002 as monotherapy and in combination with anti-PD-1 antibody toripalimab for advanced solid tumors. This multicenter, phase I trial enrolled patients with histologically or cytologically confirmed advanced solid tumors. This study included three phases: Ia (dose-escalation of RMX1002 monotherapy from 200 to 650 mg BID), Ib (dose-escalation from 500 to 650 mg BID in combination with toripalimab), and Ic (dose-expansion of 500 mg BID with toripalimab). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. A total of 45 patients were enrolled (17 in phase Ia, 12 in phase Ib, and 16 in phase Ic). No dose-limiting toxicity was reported, and the MTD was not reached. Overall, 21 patients experienced RMX1002-related adverse events with CTCAE grade ≥ 3. Pharmacokinetics revealed rapid absorption of RMX1002 with the maximum concentration (Cmax) reached within 2 to 5 h, and dose-dependent increases in Cmax and area under the concentration-time curve. The increase in urinary metabolite of PGE2 suggested the inhibition of EP4 signaling pathway. The best response was stable disease, reported in 64.7%, 28.6%, and 18.8% of patients in phase Ia, Ib, and Ic, respectively. RMX1002 was well tolerated and showed a best response of stable disease. RMX1002 500 mg BID with toripalimab 240 mg every 3 weeks is the recommended dose for future trials.
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MESH Headings
- Humans
- Male
- Female
- Middle Aged
- Neoplasms/drug therapy
- Neoplasms/metabolism
- Aged
- Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors
- Adult
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/pharmacokinetics
- Antibodies, Monoclonal, Humanized/therapeutic use
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- Dose-Response Relationship, Drug
- Antineoplastic Agents/pharmacokinetics
- Antineoplastic Agents/administration & dosage
- Antineoplastic Agents/adverse effects
- Antineoplastic Agents/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Aged, 80 and over
- Maximum Tolerated Dose
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Affiliation(s)
- Dan Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Center, Peking University Cancer Hospital and Institute, Hai-Dian District, Beijing, 100142, China
| | - Jifang Gong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Center, Peking University Cancer Hospital and Institute, Hai-Dian District, Beijing, 100142, China
| | - Jian Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210003, China
| | - Hao Wu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210003, China
| | - Tianshu Liu
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200000, China
| | - Yanhua Xu
- Ningbo Newbay Pharmaceutical Technology Co., Ltd, Ningbo, 315000, China
| | - Lijia Zhang
- Ningbo Newbay Pharmaceutical Technology Co., Ltd, Ningbo, 315000, China
| | - Min Li
- Ningbo Newbay Pharmaceutical Technology Co., Ltd, Ningbo, 315000, China
| | - Xichun Hu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- , 52 Fucheng Road, Haidian District, Beijing, 100142, China.
| | - Lin Shen
- , 399 Lingling Road, Xuhui District, Shanghai, 200000, China.
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
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3
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Arora D, Vanshita, Bhati H, Bansal K. Recent advancements in genistein nanocarrier systems for effective cancer management. Med Oncol 2025; 42:101. [PMID: 40072692 DOI: 10.1007/s12032-025-02649-w] [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: 10/22/2024] [Accepted: 02/24/2025] [Indexed: 03/14/2025]
Abstract
Cancer continues to be a significant global health concern, consistently ranking as one of the leading causes of mortality across diverse populations and socio-economic contexts. Genistein, a soy-derived isoflavonoid, has gained significant attention for its diverse health benefits, particularly its potent anticancer activity. Emerging pre-clinical and clinical evidences highlights its ability to modulate key cellular processes, including apoptosis, autophagy, angiogenesis, metastasis, immune responses and cell cycle regulation. Despite its therapeutic potential, the clinical translation of genistein is limited by its poor pharmacokinetics, low aqueous solubility, and rapid metabolic degradation, resulting in suboptimal bioavailability. To address these limitations, various nanotechnology-based formulations have been developed, significantly improving the bioavailability, stability, and therapeutic efficacy of genistein. Functionalized nanocarriers further enhance its effectiveness by enabling targeted drug delivery, reducing off-target toxicities, and achieving sustained release at the tumor site. This review provides a comprehensive overview of advanced nanoformulations for genistein delivery emphasizing their efficacy against prevalent cancers such as breast, lung, and colon cancer. By exploring the interplay between genistein's therapeutic potential and innovative drug delivery systems, this review underscores the transformative impact of nanotechnology in overcoming the limitations of conventional cancer therapies and improving patience compliance.
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Affiliation(s)
- Diya Arora
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, 281406, India
| | - Vanshita
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, 281406, India
| | - Hemant Bhati
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, 281406, India
| | - Keshav Bansal
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, 281406, India.
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4
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Lu W, Aihaiti A, Abudukeranmu P, Liu Y, Gao H. Arachidonic acid metabolism as a novel pathogenic factor in gastrointestinal cancers. Mol Cell Biochem 2025; 480:1225-1239. [PMID: 38963615 DOI: 10.1007/s11010-024-05057-2] [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: 05/27/2024] [Accepted: 06/25/2024] [Indexed: 07/05/2024]
Abstract
Gastrointestinal (GI) cancers are a major global health burden, representing 20% of all cancer diagnoses and 22.5% of global cancer-related deaths. Their aggressive nature and resistance to treatment pose a significant challenge, with late-stage survival rates below 15% at five years. Therefore, there is an urgent need to delve deeper into the mechanisms of gastrointestinal cancer progression and optimize treatment strategies. Increasing evidence highlights the active involvement of abnormal arachidonic acid (AA) metabolism in various cancers. AA is a fatty acid mainly metabolized into diverse bioactive compounds by three enzymes: cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes. Abnormal AA metabolism and altered levels of its metabolites may play a pivotal role in the development of GI cancers. However, the underlying mechanisms remain unclear. This review highlights a unique perspective by focusing on the abnormal metabolism of AA and its involvement in GI cancers. We summarize the latest advancements in understanding AA metabolism in GI cancers, outlining changes in AA levels and their potential role in liver, colorectal, pancreatic, esophageal, gastric, and gallbladder cancers. Moreover, we also explore the potential of targeting abnormal AA metabolism for future therapies, considering the current need to explore AA metabolism in GI cancers and outlining promising avenues for further research. Ultimately, such investigations aim to improve treatment options for patients with GI cancers and pave the way for better cancer management in this area.
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Affiliation(s)
- Weiqin Lu
- General Surgery, Cancer Center, Department of Vascular Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | | | | | - Yajun Liu
- Aksu First People's Hospital, Xinjiang, China
| | - Huihui Gao
- Cancer Center, Department of Hospital Infection Management and Preventive Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
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5
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Sharma U, Sahu A, Shekhar H, Sharma B, Haque S, Kaur D, Tuli HS, Mishra A, Ahmad F. The heat of the battle: inflammation's role in prostate cancer development and inflammation-targeted therapies. Discov Oncol 2025; 16:108. [PMID: 39891849 PMCID: PMC11787145 DOI: 10.1007/s12672-025-01829-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/16/2025] [Indexed: 02/03/2025] Open
Abstract
In prostate cancer (PC), chronic inflammation silently guides disease progression, playing a significant role. As a major global health concern, PC contributes to high mortality rates and rising new cases worldwide, highlighting the urgent need for research into the molecular mechanisms behind this disease. Notably, the persistence of inflammation actively promotes cancer development, including in PC. This review explores the complex relationship between inflammation and PC, examining the molecular pathways, genetic and environmental factors, and clinical implications involved in inflammation-driven carcinogenesis. From cellular and molecular elements of the inflammatory microenvironment to mechanisms like epithelial-to-mesenchymal transition (EMT), reactive oxygen species (ROS) generation, and inflammasome activation, these processes highlight inflammation's influence on PC progression and metastasis. Furthermore, this review discusses current therapeutic strategies targeting inflammation in PC management and identifies future research directions aimed at unraveling the complexities of inflammation-induced PC (Supplementary Fig. 1). It defines the complex relationship between inflammation and PC, emphasizes the importance of targeting inflammation therapeutically and highlights innovative approaches in PC treatment.
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Affiliation(s)
- Ujjawal Sharma
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bhatinda, 151001, India
| | - Anidrisha Sahu
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bhatinda, 151001, India
| | - Himanshu Shekhar
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bhatinda, 151001, India
| | - Bunty Sharma
- Department of Biotechnology, Graphic Era (Deemed to be University), Dehradun, Uttarakhand, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Health Sciences, Jazan University, 45142, Jazan, Saudi Arabia
- School of Medicine, Universidad Espiritu Santo, Samborondon, 091952, Ecuador
| | - Damandeep Kaur
- University Centre for Research & Development, University Institute of Pharmaceutical Sciences, Chandigarh University, Gharuan, Mohali, Punjab, 140413, India
| | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, 133207, India
| | - Astha Mishra
- Department of Optometry, Chitkara School of Health Sciences, Chitkara University, Rajpura, Punjab, India
| | - Faraz Ahmad
- Department of Biotechnology, School of Bio Sciences and Technology (SBST), Vellore Institute of Technology, Vellore, 632014, India.
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6
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Xie R, Luo Y, Bao B, Wu X, Guo J, Wang J, Qu X, Che X, Zheng C. The Role of Fatty Acid Metabolism, the Related Potential Biomarkers, and Targeted Therapeutic Strategies in Gastrointestinal Cancers. Drug Dev Res 2024; 85:e70014. [PMID: 39527665 DOI: 10.1002/ddr.70014] [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: 05/17/2024] [Revised: 10/12/2024] [Accepted: 10/13/2024] [Indexed: 11/16/2024]
Abstract
Gastrointestinal cancer has emerged as a significant global health concern due to its high incidence and mortality, limited effectiveness of early detection, suboptimal treatment outcomes, and poor prognosis. Metabolic reprogramming is a prominent feature of cancer, and fatty acid metabolism assumes a pivotal role in bridging glucose metabolism and lipid metabolism. Fatty acids play important roles in cellular structural composition, energy supply, signal transduction, and other lipid-related processes. Changes in the levels of fatty acid metabolite may indicate the malignant transformation of gastrointestinal cells, which have an impact on the prognosis of patients and can be used as a marker to monitor the efficacy of anticancer therapy. Therefore, targeting key enzymes involved in fatty acid metabolism, either as monotherapy or in combination with other agents, is a promising strategy for anticancer treatment. This article reviews the potential mechanisms of fatty acid metabolism disorders in the occurrence and development of gastrointestinal tumors, and summarizes the related potential biomarkers and anticancer strategies.
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Affiliation(s)
- Ruixi Xie
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ying Luo
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Bowen Bao
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xinshu Wu
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jia Guo
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jin Wang
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiujuan Qu
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaofang Che
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chunlei Zheng
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Department of Oncology, Shanghai Electric Power Hospital, Shanghai, China
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7
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Manoochehri H, Farrokhnia M, Sheykhhasan M, Mahaki H, Tanzadehpanah H. Key target genes related to anti-breast cancer activity of ATRA: A network pharmacology, molecular docking and experimental investigation. Heliyon 2024; 10:e34300. [PMID: 39108872 PMCID: PMC11301165 DOI: 10.1016/j.heliyon.2024.e34300] [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: 04/17/2024] [Revised: 07/05/2024] [Accepted: 07/08/2024] [Indexed: 01/07/2025] Open
Abstract
All-trans retinoic acid (ATRA) has promising activity against breast cancer. However, the exact mechanisms of ATRA's anticancer effects remain complex and not fully understood. In this study, a network pharmacology and molecular docking approach was applied to identify key target genes related to ATRA's anti-breast cancer activity. Gene/disease enrichment analysis for predicted ATRA targets was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID), the Comparative Toxicogenomics Database (CTD), and the Gene Set Cancer Analysis (GSCA) database. Protein-Protein Interaction Network (PPIN) generation and analysis was conducted via Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and cytoscape, respectively. Cancer-associated genes were evaluated using MyGeneVenn from the CTD. Differential expression analysis was conducted using the Tumor, Normal, and Metastatic (TNM) Plot tool and the Human Protein Atlas (HPA). The Glide docking program was used to predict ligand-protein binding. Treatment response predication and clinical profile assessment were performed using Receiver Operating Characteristic (ROC) Plotter and OncoDB databases, respectively. Cytotoxicity and gene expression were measured using MTT/fluorescent assays and Real-Time PCR, respectively. Molecular functions of ATRA targets (n = 209) included eicosanoid receptor activity and transcription factor activity. Some enriched pathways included inclusion body myositis and nuclear receptors pathways. Network analysis revealed 35 hub genes contributing to 3 modules, with 16 of them were associated with breast cancer. These genes were involved in apoptosis, cell cycle, androgen receptor pathway, and ESR-mediated signaling, among others. CCND1, ESR1, MMP9, MDM2, NCOA3, and RARA were significantly overexpressed in tumor samples. ATRA showed a high affinity towards CCND1/CDK4 and MMP9. CCND1, ESR1, and MDM2 were associated with poor treatment response and were downregulated after treatment of the breast cancer cell line with ATRA. CCND1 and ESR1 exhibited differential expression across breast cancer stages. Therefore, some part of ATRA's anti-breast cancer activity may be exerted through the CCND1/CDK4 complex.
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Affiliation(s)
- Hamed Manoochehri
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Maryam Farrokhnia
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Mohsen Sheykhhasan
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Hanie Mahaki
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Tanzadehpanah
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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8
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Luís JM, Files R, Cardoso C, Pimenta J, Maia G, Silva F, Queiroga FL, Prada J, Pires I. Immunohistochemical Expression Levels of Epidermal Growth Factor Receptor, Cyclooxygenase-2, and Ki-67 in Canine Cutaneous Squamous Cell Carcinomas. Curr Issues Mol Biol 2024; 46:4951-4967. [PMID: 38785565 PMCID: PMC11119584 DOI: 10.3390/cimb46050297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/07/2024] [Accepted: 05/16/2024] [Indexed: 05/25/2024] Open
Abstract
Squamous cell carcinoma (SCC) stands as the second most prevalent skin cancer in dogs, primarily attributed to UV radiation exposure. Affected areas typically include regions with sparse hair and pale or depigmented skin. The significance of spontaneous canine cutaneous SCC as a model for its human counterpart is underscored by its resemblance. This study assesses the expression of key markers-Epidermal Growth Factor Receptor (EGFR), Cyclooxygenase-2 (Cox-2), and Ki-67-in canine cutaneous SCC. Our objective is to investigate the association between their expression levels and classical clinicopathological parameters, unraveling the intricate relationships among these molecular markers. In our retrospective analysis of 37 cases, EGFR overexpression manifested in 43.2% of cases, while Cox-2 exhibited overexpression in 97.3%. The EGFR, Cox-2 overexpression, and Ki-67 proliferation indices, estimated through immunohistochemistry, displayed a significant association with the histological grade, but only EGFR labeling is associated with the presence of lymphovascular emboli. The Ki-67 labeling index expression exhibited an association with EGFR and Cox-2. These findings propose that EGFR, Cox-2, and Ki-67 hold promise as valuable markers in canine SCC. EGFR, Cox-2, and Ki-67 may serve as indicators of disease progression, offering insights into the malignancy of a lesion. The implications extend to the potential therapeutic targeting of EGFR and Cox-2 in managing canine SCC. Further exploration of these insights is warranted due to their translational relevance and the development of targeted interventions in the context of canine SCC.
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Affiliation(s)
- João Miguel Luís
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal; (J.M.L.); (R.F.); (G.M.); (J.P.)
| | - Rita Files
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal; (J.M.L.); (R.F.); (G.M.); (J.P.)
| | - Cláudia Cardoso
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal; (J.M.L.); (R.F.); (G.M.); (J.P.)
| | - José Pimenta
- Animal and Veterinary Research Centre (CECAV) and Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal;
- CIVG—Vasco da Gama Research Center/EUVG, Vasco da Gama University School, 3020-210 Coimbra, Portugal
| | - Gabriela Maia
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal; (J.M.L.); (R.F.); (G.M.); (J.P.)
| | - Filipe Silva
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal; (J.M.L.); (R.F.); (G.M.); (J.P.)
- Animal and Veterinary Research Centre (CECAV) and Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal;
| | - Felisbina L. Queiroga
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal; (J.M.L.); (R.F.); (G.M.); (J.P.)
- Animal and Veterinary Research Centre (CECAV) and Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal;
- Centre for the Study of Animal Science, CECA-ICETA, University of Porto, 4099-002 Porto, Portugal
| | - Justina Prada
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal; (J.M.L.); (R.F.); (G.M.); (J.P.)
- Animal and Veterinary Research Centre (CECAV) and Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal;
| | - Isabel Pires
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal; (J.M.L.); (R.F.); (G.M.); (J.P.)
- Animal and Veterinary Research Centre (CECAV) and Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal;
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9
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Ferreira T, Faustino-Rocha AI, Gaspar VM, Medeiros R, Mano JF, Oliveira PA. Contribution of non-steroidal anti-inflammatory drugs to breast cancer treatment: In vitro and in vivo studies. Vet World 2024; 17:1052-1072. [PMID: 38911075 PMCID: PMC11188899 DOI: 10.14202/vetworld.2024.1052-1072] [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: 11/02/2023] [Accepted: 04/19/2024] [Indexed: 06/25/2024] Open
Abstract
Chronic inflammation plays a crucial role in carcinogenesis. High levels of serum prostaglandin E2 and tissue overexpression of cyclooxygenase-2 (COX-2) have been described in breast, urinary, colorectal, prostate, and lung cancers as being involved in tumor initiation, promotion, progression, angiogenesis, and immunosuppression. Non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed for several medical conditions to not only decrease pain and fever but also reduce inflammation by inhibiting COX and its product synthesis. To date, significant efforts have been made to better understand and clarify the interplay between cancer development, inflammation, and NSAIDs with a view toward addressing their potential for cancer management. This review provides readers with an overview of the potential use of NSAIDs and selective COX-2 inhibitors for breast cancer treatment, highlighting pre-clinical in vitro and in vivo studies employed to evaluate the efficacy of NSAIDs and their use in combination with other antineoplastic drugs.
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Affiliation(s)
- Tiago Ferreira
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production (Inov4Agro), UTAD, 5000–801 Vila Real, Portugal
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto), Porto Comprehensive Cancer Center (Porto. CCC), 4200–072 Porto, Portugal
- Department of Chemistry, Aveiro Institute of Materials (CICECO), University of Aveiro, Campus Universitário de Santiago, 3810–193, Aveiro, Portugal
| | - Ana I. Faustino-Rocha
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production (Inov4Agro), UTAD, 5000–801 Vila Real, Portugal
- Department of Zootechnics, School of Sciences and Technology, University of Évora, Évora 7004-516, Portugal
- Comprehensive Health Research Center, 7004–516 Évora, Portugal
| | - Vítor M. Gaspar
- Department of Chemistry, Aveiro Institute of Materials (CICECO), University of Aveiro, Campus Universitário de Santiago, 3810–193, Aveiro, Portugal
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto), Porto Comprehensive Cancer Center (Porto. CCC), 4200–072 Porto, Portugal
- Faculty of Medicine of the University of Porto, 4200–319 Porto, Portugal
- Department of Research, Portuguese League against Cancer-Regional Nucleus of the North (Liga Portuguesa Contra o Cancro-Núcleo Regional do Norte), 4200–177 Porto, Portugal
- Virology Service, IPO Porto, 4200-072 Porto, Portugal
- Biomedical Research Center (CEBIMED), Faculty of Health Sciences, Fernando Pessoa University, Porto 4249-004, Portugal
| | - João F. Mano
- Department of Chemistry, Aveiro Institute of Materials (CICECO), University of Aveiro, Campus Universitário de Santiago, 3810–193, Aveiro, Portugal
| | - Paula A. Oliveira
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production (Inov4Agro), UTAD, 5000–801 Vila Real, Portugal
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Gomaa M, Gad W, Hussein D, Pottoo FH, Tawfeeq N, Alturki M, Alfahad D, Alanazi R, Salama I, Aziz M, Zahra A, Hanafy A. Sulfadiazine Exerts Potential Anticancer Effect in HepG2 and MCF7 Cells by Inhibiting TNFα, IL1b, COX-1, COX-2, 5-LOX Gene Expression: Evidence from In Vitro and Computational Studies. Pharmaceuticals (Basel) 2024; 17:189. [PMID: 38399404 PMCID: PMC10891904 DOI: 10.3390/ph17020189] [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: 01/02/2024] [Revised: 01/24/2024] [Accepted: 01/28/2024] [Indexed: 02/25/2024] Open
Abstract
Drug repurposing is a promising approach that has the potential to revolutionize the drug discovery and development process. By leveraging existing drugs, we can bring new treatments to patients more quickly and affordably. Anti-inflammatory drugs have been shown to target multiple pathways involved in cancer development and progression. This suggests that they may be more effective in treating cancer than drugs that target a single pathway. Cell viability was measured using the MTT assay. The expression of genes related to inflammation (TNFa, IL1b, COX-1, COX-2, and 5-LOX) was measured in HepG2, MCF7, and THLE-2 cells using qPCR. The levels of TNFα, IL1b, COX-1, COX-2, and 5-LOX were also measured in these cells using an ELISA kit. An enzyme binding assay revealed that sulfadiazine expressed weaker inhibitory activity against COX-2 (IC50 = 5.27 μM) in comparison with the COX-2 selective reference inhibitor celecoxib (COX-2 IC50 = 1.94 μM). However, a more balanced inhibitory effect was revealed for sulfadiazine against the COX/LOX pathway with greater affinity towards 5-LOX (IC50 = 19.1 μM) versus COX-1 (IC50 = 18.4 μM) as compared to celecoxib (5-LOX IC50 = 16.7 μM, and COX-1 IC50 = 5.9 μM). MTT assays revealed the IC50 values of 245.69 ± 4.1 µM and 215.68 ± 3.8 µM on HepG2 and MCF7 cell lines, respectively, compared to the standard drug cisplatin (66.92 ± 1.8 µM and 46.83 ± 1.3 µM, respectively). The anti-inflammatory effect of sulfadiazine was also depicted through its effect on the levels of inflammatory markers and inflammation-related genes (TNFα, IL1b, COX-1, COX-2, 5-LOX). Molecular simulation studies revealed key binding interactions that explain the difference in the activity profiles of sulfadiazine compared to celecoxib. The results suggest that sulfadiazine exhibited balanced inhibitory activity against the 5-LOX/COX-1 enzymes compared to the selective COX-2 inhibitor, celecoxib. These findings highlight the potential of sulfadiazine as a potential anticancer agent through balanced inhibitory activity against the COX/LOX pathway and reduction in the expression of inflammatory genes.
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Affiliation(s)
- Mohamed Gomaa
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia; (N.T.); (M.A.)
| | - Wael Gad
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh 6860404, Egypt; (W.G.); (M.A.); (A.Z.); (A.H.)
| | - Dania Hussein
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia;
| | - Faheem Hyder Pottoo
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia;
| | - Nada Tawfeeq
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia; (N.T.); (M.A.)
| | - Mansour Alturki
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia; (N.T.); (M.A.)
| | - Dhay Alfahad
- College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia; (D.A.); (R.A.)
| | - Razan Alanazi
- College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia; (D.A.); (R.A.)
| | - Ismail Salama
- Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 8366004, Egypt;
| | - Mostafa Aziz
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh 6860404, Egypt; (W.G.); (M.A.); (A.Z.); (A.H.)
| | - Aboelnasr Zahra
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh 6860404, Egypt; (W.G.); (M.A.); (A.Z.); (A.H.)
| | - Abeer Hanafy
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh 6860404, Egypt; (W.G.); (M.A.); (A.Z.); (A.H.)
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11
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Fadaly WAA, Nemr MTM, Zidan TH, Mohamed FEA, Abdelhakeem MM, Abu Jayab NN, Omar HA, Abdellatif KRA. New 1,2,3-triazole/1,2,4-triazole hybrids linked to oxime moiety as nitric oxide donor selective COX-2, aromatase, B-RAF V600E and EGFR inhibitors celecoxib analogs: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis and molecular modeling study. J Enzyme Inhib Med Chem 2023; 38:2290461. [PMID: 38061801 PMCID: PMC11003496 DOI: 10.1080/14756366.2023.2290461] [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: 06/03/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
A new series of bis-triazole 19a-l was synthesised for the purpose of being hybrid molecules with both anti-inflammatory and anti-cancer activities and assessed for cell cycle arrest, NO release. Compounds 19c, 19f, 19h, 19 l exhibited COX-2 selectivity indexes in the range of 18.48 to 49.38 compared to celecoxib S.I. = 21.10), inhibit MCF-7 with IC50 = 9-16 μM compared to tamoxifen (IC50 = 27.9 μM). and showed good inhibitory activity against HEP-3B with IC50 = 4.5-14 μM compared to sorafenib (IC50 = 3.5 μM) (HEP-3B). Moreover, derivatives 19e, 19j, 19k, 19 l inhibit HCT-116 with IC50 = 5.3-13.7 μM compared to 5-FU with IC50 = 4.8 μM (HCT-116). Compounds 19c, 19f, 19h, 19 l showed excellent inhibitory activity against A549 with IC50 = 3-4.5 μM compared to 5-FU with IC50 = 6 μM (A549). Compounds 19c, 19f, 19h, 19 l inhibit aromatase (IC50 of 22.40, 23.20, 22.70, 30.30 μM), EGFR (IC50 of 0.112, 0.205, 0.169 and 0.066 μM) and B-RAFV600E (IC50 of 0.09, 0.06, 0.07 and 0.05 μM).
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Affiliation(s)
- Wael A A Fadaly
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Mohamed T M Nemr
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Taha H Zidan
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Fatma E A Mohamed
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Marwa M Abdelhakeem
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Nour N Abu Jayab
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Hany A Omar
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Pharmacology Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Khaled R A Abdellatif
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
- Pharmaceutical Sciences Department, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia
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12
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Fadaly WAA, Zidan TH, Kahk NM, Mohamed FEA, Abdelhakeem MM, Khalil RG, Nemr MTM. New pyrazolyl-thiazolidinone/thiazole derivatives as celecoxib/dasatinib analogues with selective COX-2, HER-2 and EGFR inhibitory effects: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis, molecular modelling and ADME studies. J Enzyme Inhib Med Chem 2023; 38:2281262. [PMID: 38010912 PMCID: PMC11003491 DOI: 10.1080/14756366.2023.2281262] [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: 09/14/2023] [Accepted: 11/05/2023] [Indexed: 11/29/2023] Open
Abstract
Two new series of pyrazolyl-thiazolidinone/thiazole derivatives 16a-b and 18a-j were synthesised, merging the scaffolds of celecoxib and dasatinib. Compounds 16a, 16b and 18f inhibit COX-2 with S.I. 134.6, 26.08 and 42.13 respectively (celecoxib S.I. = 24.09). Compounds 16a, 16b, 18c, 18d and 18f inhibit MCF-7 with IC50 = 0.73-6.25 μM (dasatinib IC50 = 7.99 μM) and (doxorubicin IC50 = 3.1 μM) and inhibit A549 with IC50 = 1.64-14.3 μM (dasatinib IC50 = 11.8 μM and doxorubicin IC50 = 2.42 μM) with S.I. (F180/MCF7) of 33.15, 7.13, 18.72, 13.25 and 8.28 respectively higher than dasatinib (4.03) and doxorubicin (3.02) and S.I. (F180/A549) of 14.75, 12.96, 4.16, 7.07 and 18.88 respectively higher than that of dasatinib (S.I. = 2.72) and doxorubicin (S.I = 3.88). Derivatives 16a, 18c, 18d, 18f inhibit EGFR and HER-2 IC50 for EGFR of 0.043, 0.226, 0.388, 0.19 μM respectively and for HER-2 of 0.032, 0.144, 0.195, 0.201 μM respectively.
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Affiliation(s)
- Wael A. A. Fadaly
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Taha H. Zidan
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Nesma M. Kahk
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Fatma E. A. Mohamed
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Marwa M. Abdelhakeem
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Rehab G. Khalil
- Immunology Division, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Mohamed T. M. Nemr
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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13
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Cotino-Nájera S, Herrera LA, Domínguez-Gómez G, Díaz-Chávez J. Molecular mechanisms of resveratrol as chemo and radiosensitizer in cancer. Front Pharmacol 2023; 14:1287505. [PMID: 38026933 PMCID: PMC10667487 DOI: 10.3389/fphar.2023.1287505] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 10/30/2023] [Indexed: 12/01/2023] Open
Abstract
One of the primary diseases that cause death worldwide is cancer. Cancer cells can be intrinsically resistant or acquire resistance to therapies and drugs used for cancer treatment through multiple mechanisms of action that favor cell survival and proliferation, becoming one of the leading causes of treatment failure against cancer. A promising strategy to overcome chemoresistance and radioresistance is the co-administration of anticancer agents and natural compounds with anticancer properties, such as the polyphenolic compound resveratrol (RSV). RSV has been reported to be able to sensitize cancer cells to chemotherapeutic agents and radiotherapy, promoting cancer cell death. This review describes the reported molecular mechanisms by which RSV sensitizes tumor cells to radiotherapy and chemotherapy treatment.
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Affiliation(s)
- Sandra Cotino-Nájera
- Laboratorio de Oncología Molecular, Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Ciudad de México, Mexico
| | - Luis A. Herrera
- Laboratorio de Oncología Molecular, Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Ciudad de México, Mexico
- Escuela de Medicina y Ciencias de la Salud-Tecnológico de Monterrey, México City, Mexico
| | - Guadalupe Domínguez-Gómez
- Subdirección de Investigación Clínica, Instituto Nacional de Cancerología (INCAN), Ciudad de México, Mexico
| | - José Díaz-Chávez
- Unidad de Investigación en Cáncer, Instituto de Investigaciones Biomédicas-Universidad Nacional Autónoma de México, Instituto Nacional de Cancerología, Ciudad de México, Mexico
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14
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Zhou Q, Xiang J, Qiu N, Wang Y, Piao Y, Shao S, Tang J, Zhou Z, Shen Y. Tumor Abnormality-Oriented Nanomedicine Design. Chem Rev 2023; 123:10920-10989. [PMID: 37713432 DOI: 10.1021/acs.chemrev.3c00062] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/17/2023]
Abstract
Anticancer nanomedicines have been proven effective in mitigating the side effects of chemotherapeutic drugs. However, challenges remain in augmenting their therapeutic efficacy. Nanomedicines responsive to the pathological abnormalities in the tumor microenvironment (TME) are expected to overcome the biological limitations of conventional nanomedicines, enhance the therapeutic efficacies, and further reduce the side effects. This Review aims to quantitate the various pathological abnormalities in the TME, which may serve as unique endogenous stimuli for the design of stimuli-responsive nanomedicines, and to provide a broad and objective perspective on the current understanding of stimuli-responsive nanomedicines for cancer treatment. We dissect the typical transport process and barriers of cancer drug delivery, highlight the key design principles of stimuli-responsive nanomedicines designed to tackle the series of barriers in the typical drug delivery process, and discuss the "all-into-one" and "one-for-all" strategies for integrating the needed properties for nanomedicines. Ultimately, we provide insight into the challenges and future perspectives toward the clinical translation of stimuli-responsive nanomedicines.
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Affiliation(s)
- Quan Zhou
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Department of Cell Biology, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Jiajia Xiang
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Department of Cell Biology, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Nasha Qiu
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Yechun Wang
- Department of Cell Biology, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Ying Piao
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Shiqun Shao
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Jianbin Tang
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Zhuxian Zhou
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Youqing Shen
- Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
- State Key Laboratory of Chemical Engineering, Zhejiang University, Hangzhou 310058, China
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15
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Jin K, Qian C, Lin J, Liu B. Cyclooxygenase-2-Prostaglandin E2 pathway: A key player in tumor-associated immune cells. Front Oncol 2023; 13:1099811. [PMID: 36776289 PMCID: PMC9911818 DOI: 10.3389/fonc.2023.1099811] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 01/12/2023] [Indexed: 01/29/2023] Open
Abstract
Cyclooxygenases-2 (COX-2) and Prostaglandin E2 (PGE2), which are important in chronic inflammatory diseases, can increase tumor incidence and promote tumor growth and metastasis. PGE2 binds to various prostaglandin E receptors to activate specific downstream signaling pathways such as PKA pathway, β-catenin pathway, NF-κB pathway and PI3K/AKT pathway, all of which play important roles in biological and pathological behavior. Nonsteroidal anti-inflammatory drugs (NSAIDs), which play as COX-2 inhibitors, and EP antagonists are important in anti-tumor immune evasion. The COX-2-PGE2 pathway promotes tumor immune evasion by regulating myeloid-derived suppressor cells, lymphocytes (CD8+ T cells, CD4+ T cells and natural killer cells), and antigen presenting cells (macrophages and dendritic cells). Based on conventional treatment, the addition of COX-2 inhibitors or EP antagonists may enhance immunotherapy response in anti-tumor immune escape. However, there are still a lot of challenges in cancer immunotherapy. In this review, we focus on how the COX-2-PGE2 pathway affects tumor-associated immune cells.
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Affiliation(s)
- Kaipeng Jin
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Chao Qian
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jinti Lin
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China,*Correspondence: Bing Liu, ; Jinti Lin,
| | - Bing Liu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China,*Correspondence: Bing Liu, ; Jinti Lin,
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16
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Dean PT, Hooks SB. Pleiotropic effects of the COX-2/PGE2 axis in the glioblastoma tumor microenvironment. Front Oncol 2023; 12:1116014. [PMID: 36776369 PMCID: PMC9909545 DOI: 10.3389/fonc.2022.1116014] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 12/19/2022] [Indexed: 01/27/2023] Open
Abstract
Glioblastoma (GBM) is the most common and aggressive form of malignant glioma. The GBM tumor microenvironment (TME) is a complex ecosystem of heterogeneous cells and signaling factors. Glioma associated macrophages and microglia (GAMs) constitute a significant portion of the TME, suggesting that their functional attributes play a crucial role in cancer homeostasis. In GBM, an elevated GAM population is associated with poor prognosis and therapeutic resistance. Neoplastic cells recruit these myeloid populations through release of chemoattractant factors and dysregulate their induction of inflammatory programs. GAMs become protumoral advocates through production a variety of cytokines, inflammatory mediators, and growth factors that can drive cancer proliferation, invasion, immune evasion, and angiogenesis. Among these inflammatory factors, cyclooxygenase-2 (COX-2) and its downstream product, prostaglandin E2 (PGE2), are highly enriched in GBM and their overexpression is positively correlated with poor prognosis in patients. Both tumor cells and GAMs have the ability to signal through the COX-2 PGE2 axis and respond in an autocrine/paracrine manner. In the GBM TME, enhanced signaling through the COX-2/PGE2 axis leads to pleotropic effects that impact GAM dynamics and drive tumor progression.
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17
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Morisaka H, Takaishi M, Akira S, Sano S. Keratinocyte Regnase-1, a Downregulator of Skin Inflammation, Contributes to Protection against Tumor Promotion by Limiting Cyclooxygenase-2 Expression. J Invest Dermatol 2022; 143:731-739. [PMID: 36470473 DOI: 10.1016/j.jid.2022.11.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/07/2022] [Accepted: 11/01/2022] [Indexed: 12/12/2022]
Abstract
We previously showed that the ribonuclease Regnase-1 (Reg1) in keratinocytes plays a role in mitigating skin inflammation by downregulating proinflammatory cytokines. In this study, we explored whether Reg1 also has a protective role against skin carcinogenesis. The chemically induced two-stage carcinogenesis protocol revealed that epidermis-specific Reg1-deficient (Reg1-knockout [Reg1-cKO]) mice developed skin tumors with shorter latency and more multiplicity than control mice. In addition, repeated UVB irradiation readily provoked solar keratosis-like lesions in Reg1-cKO mice. Increased levels of cyclooxygenase 2, whose mRNA (Ptgs2) is reportedly a target of Reg1, have been known to be associated with the development of squamous cell carcinomas. Indeed, Ptgs2 mRNA levels were upregulated in the skin of Reg1-cKO mice after treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. The level of prostaglandin E2 was higher in 12-O-tetradecanoylphorbol-13-acetate‒treated Reg1-cKO mouse skin than in control mice skin. Moreover, in vivo inhibition of cyclooxygenase 2 attenuated the 12-O-tetradecanoylphorbol-13-acetate‒induced epidermal thickening in Reg1-cKO mice. Finally, REG1 knockdown in human squamous cell carcinomas lines enhanced PTGS2 mRNA levels after 12-O-tetradecanoylphorbol-13-acetate treatment. In conclusion, epidermal Reg1 plays a regulatory role not only in skin inflammation but also in tumor promotion through the downregulation of cyclooxygenase 2. Therefore, forced expression of Reg1 under inflammatory conditions may be relevant to preventing skin cancer.
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Affiliation(s)
- Hiroyuki Morisaka
- Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Mikiro Takaishi
- Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Shizuo Akira
- Laboratory of Host Defense, Immunology Frontier Research Center, World Premier Institute for Immunology, Osaka University, Suita, Japan; Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
| | - Shigetoshi Sano
- Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Japan.
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Choi SYC, Ribeiro CF, Wang Y, Loda M, Plymate SR, Uo T. Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer. Biomolecules 2022; 12:1590. [PMID: 36358940 PMCID: PMC9687810 DOI: 10.3390/biom12111590] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 08/27/2023] Open
Abstract
There is an urgent need for exploring new actionable targets other than androgen receptor to improve outcome from lethal castration-resistant prostate cancer. Tumor metabolism has reemerged as a hallmark of cancer that drives and supports oncogenesis. In this regard, it is important to understand the relationship between distinctive metabolic features, androgen receptor signaling, genetic drivers in prostate cancer, and the tumor microenvironment (symbiotic and competitive metabolic interactions) to identify metabolic vulnerabilities. We explore the links between metabolism and gene regulation, and thus the unique metabolic signatures that define the malignant phenotypes at given stages of prostate tumor progression. We also provide an overview of current metabolism-based pharmacological strategies to be developed or repurposed for metabolism-based therapeutics for castration-resistant prostate cancer.
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Affiliation(s)
- Stephen Y. C. Choi
- Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
- Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada
- Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Caroline Fidalgo Ribeiro
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY 10021, USA
| | - Yuzhuo Wang
- Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
- Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada
- Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Massimo Loda
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY 10021, USA
- New York Genome Center, New York, NY 10013, USA
| | - Stephen R. Plymate
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, 850 Republican St., Seattle, WA 98109, USA
- Geriatrics Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA
| | - Takuma Uo
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, 850 Republican St., Seattle, WA 98109, USA
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Raaijmakers TK, van den Bijgaart RJE, Scheffer GJ, Ansems M, Adema GJ. NSAIDs affect dendritic cell cytokine production. PLoS One 2022; 17:e0275906. [PMID: 36227963 PMCID: PMC9560552 DOI: 10.1371/journal.pone.0275906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 09/26/2022] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Immunotherapy is now considered as the new pillar in treatment of cancer patients. Dendritic cells (DCs) play an essential role in stimulating anti-tumor immune responses, as they are capable of cross-presenting exogenous tumor antigens in MHCI complexes to activate naïve CD8+ T cells. Analgesics, like non-steroid anti-inflammatory drugs (NSAIDs), are frequently given to cancer patients to help relieve pain, however little is known about their impact on DC function. METHODS Here, we investigated the effect of the NSAIDs diclofenac, ibuprofen and celecoxib on the three key processes of DCs required for proper CD8+ cytotoxic T cell induction: antigen cross-presentation, co-stimulatory marker expression, and cytokine production. RESULTS Our results show that TLR-induced pro- and anti-inflammatory cytokine excretion by human monocyte derived and murine bone-marrow derived DCs is diminished after NSAID exposure. CONCLUSIONS These results indicate that various NSAIDs can affect DC function and warrant further investigation into the impact of NSAIDs on DC priming of T cells and cancer immunotherapy efficacy.
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Affiliation(s)
- Tonke K. Raaijmakers
- Department of Radiation Oncology, Radiotherapy & OncoImmunology Laboratory, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, The Netherlands
- Department of Anesthesiology, Pain and Palliative Medicine, Radboud UMC, Nijmegen, The Netherlands
| | - Renske J. E. van den Bijgaart
- Department of Radiation Oncology, Radiotherapy & OncoImmunology Laboratory, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, The Netherlands
| | - Gert Jan Scheffer
- Department of Anesthesiology, Pain and Palliative Medicine, Radboud UMC, Nijmegen, The Netherlands
| | - Marleen Ansems
- Department of Radiation Oncology, Radiotherapy & OncoImmunology Laboratory, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, The Netherlands
| | - Gosse J. Adema
- Department of Radiation Oncology, Radiotherapy & OncoImmunology Laboratory, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, The Netherlands
- * E-mail:
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20
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Yang X, Niu Z, Wang X, Lu X, Sun J, Carpena M, Prieto M, Simal-Gandara J, Xiao J, Liu C, Li N. The Nutritional and Bioactive Components, Potential Health Function and Comprehensive Utilization of Pomegranate: A Review. FOOD REVIEWS INTERNATIONAL 2022. [DOI: 10.1080/87559129.2022.2110260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Xuhan Yang
- Key Laboratory of Food Processing Technology and Quality Control in Shandong Province, College of Food Science and Engineering, Shandong Agricultural University, Tai’an, China
| | - Zhonglu Niu
- Key Laboratory of Food Processing Technology and Quality Control in Shandong Province, College of Food Science and Engineering, Shandong Agricultural University, Tai’an, China
| | - Xiaorui Wang
- Key Laboratory of Food Processing Technology and Quality Control in Shandong Province, College of Food Science and Engineering, Shandong Agricultural University, Tai’an, China
| | - Xiaoming Lu
- Key Laboratory of Food Processing Technology and Quality Control in Shandong Province, College of Food Science and Engineering, Shandong Agricultural University, Tai’an, China
| | - Jinyue Sun
- Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Key Laboratory of Agro-Products Processing Technology of Shandong Province/Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, Jinan, China
| | - M. Carpena
- Faculty of Science, Department of Analytical Chemistry and Food Science, Universidade de Vigo, Nutrition and Bromatology Group, Ourense, Spain
| | - M.A. Prieto
- Faculty of Science, Department of Analytical Chemistry and Food Science, Universidade de Vigo, Nutrition and Bromatology Group, Ourense, Spain
| | - Jesus Simal-Gandara
- Faculty of Science, Department of Analytical Chemistry and Food Science, Universidade de Vigo, Nutrition and Bromatology Group, Ourense, Spain
| | - Jianbo Xiao
- Faculty of Science, Department of Analytical Chemistry and Food Science, Universidade de Vigo, Nutrition and Bromatology Group, Ourense, Spain
| | - Chao Liu
- Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Key Laboratory of Agro-Products Processing Technology of Shandong Province/Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Ningyang Li
- Key Laboratory of Food Processing Technology and Quality Control in Shandong Province, College of Food Science and Engineering, Shandong Agricultural University, Tai’an, China
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21
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Immune Modulatory Effects of Nonsteroidal Anti-inflammatory Drugs in the Perioperative Period and Their Consequence on Postoperative Outcome. Anesthesiology 2022; 136:843-860. [PMID: 35180291 DOI: 10.1097/aln.0000000000004141] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nonsteroidal anti-inflammatory drugs are among the most commonly administered drugs in the perioperative period due to their prominent role in pain management. However, they potentially have perioperative consequences due to immune-modulating effects through the inhibition of prostanoid synthesis, thereby affecting the levels of various cytokines. These effects may have a direct impact on the postoperative outcome of patients since the immune system aims to restore homeostasis and plays an indispensable role in regeneration and repair. By affecting the immune response, consequences can be expected on various organ systems. This narrative review aims to highlight these potential immune system-related consequences, which include systemic inflammatory response syndrome, acute respiratory distress syndrome, immediate and persistent postoperative pain, effects on oncological and neurologic outcome, and wound, anastomotic, and bone healing.
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22
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Wu SR, Liu J, Zhang LF, Wang N, Zhang LY, Wu Q, Liu JY, Shi YQ. Lamb’s tripe extract and vitamin B 12 capsule plus celecoxib reverses intestinal metaplasia and atrophy: A retrospective cohort study. World J Clin Cases 2021; 9:10472-10483. [PMID: 35004979 PMCID: PMC8686147 DOI: 10.12998/wjcc.v9.i34.10472] [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: 03/27/2021] [Revised: 08/31/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic atrophic gastritis (AG) with intestinal metaplasia (IM) significantly increases the risk of gastric cancer. Some medicines have showed definite therapeutic effects in AG and IM regression.
AIM To validate the efficacy of Lamb’s tripe extract and vitamin B12 capsule (LTEVB12) initial therapy and celecoxib rescue therapy for IM and AG.
METHODS A total of 255 patients were included to receive LTEVB12 initial therapy (2 capsules each time, three times daily for 6 mo) in hospital in this study. The patients with failure of IM regression continued to receive celecoxib rescue therapy (200 mg, once daily for 6 mo). After each therapy finished, the patients underwent endoscopy and biopsy examination. The regression efficiency was assessed by the operative link on gastritis assessment (OLGA) and the operative link on the gastric intestinal metaplasia assessment (OLGIM) staging system. Logistic regression analysis was applied to identify factors associated with the curative effect.
RESULTS For LTEVB12 initial therapy, the reversal rates of IM and AG were 52.95% and 48.24%, respectively. Analogously, for celecoxib rescue therapy, the effective rates for IM and AG were 56.25% and 51.56%, respectively. The IM regression rate of complete therapy was up to 85.03%. In different OLGA and OLGIM stages of IM patients, therapeutic efficiency showed a significant difference in each group (P < 0.05). For both therapies, patients with high stages (III or IV) of both the OLGA and OLGIM evaluation systems showed a higher IM or AG regression rate than those with low stages (I or II). Among patients with high stages (OLGIM III and IV), the IM regression rate was above 70% for each therapy. Eating habits, fresh vegetable intake, and high-salt diet were identified as independent factors for the IM reversal effect of LTEVB12 therapy, especially high-salt diet (odds ratio = 1.852, P < 0.05).
CONCLUSION Monotherapy could reverse IM and AG. LTEVB12 initial therapy and celecoxib rescue therapy significantly increase the regression effect. IM may not be the point of no return among gastric precancerous lesions.
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Affiliation(s)
- Si-Ran Wu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Jie Liu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Li-Feng Zhang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Na Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Lu-Yao Zhang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Qiong Wu
- Department of Clinical Nutrition, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Jun-Ye Liu
- Department of Radiation Protective Medicine, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Yong-Quan Shi
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
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23
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Cell Proliferation and Tumor Induction by Ochratoxin A in Mouse Skin and Evaluation of Cyclin D1 and Cyclooxygenase-2 Expressions. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2021; 2021:1723486. [PMID: 34733352 PMCID: PMC8560303 DOI: 10.1155/2021/1723486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/13/2021] [Indexed: 12/02/2022]
Abstract
Motivation. Skin tumor is one of the frequent occurring forms of cancer where 2-3 million instances are reported worldwide. The ultraviolet rays along with the environmental pollutants and other contaminants can be the potential factors of skin cancer. Cyclin D1 is a serious gene included in controlling the development through the G1 phase of the cell cycle. Ochratoxin A (OTA) is a naturally existing mycotoxin which majorly occurs in food like grains. It is responsible for producing the splitting of single-strand DNA and is identified to be cancer-causing. It is established as a critical risk factor towards reproductive health in both males and females. Methodology. A single dose of ochratoxin A was used for topical application for assessment of skin tumor promotion activity, hyperplasia, ornithine decarboxylase activity, and expression of cyclin D1 and COX-2 in mouse skin. Enhancement in the synthesis of DNA, activation of the epidermal growth factor receptor, and overexpression of cyclin D1 and COX-2 were noted. Primary murine keratinocyte cell culture was cultured with Waymouth's medium. Western blot analysis and real-time polymerase chain reaction (RT-PCR) were used to detect the expression of cyclin D1 and COX-2. Chromatin immunoprecipitation (ChIP) assays were used to the association between AP-1 transcription and nuclear factor-kappaB (NF-κB) with COX-2 and cyclin D1 promoters. Results. The results found that cyclin D1 and COX-2 were responsible for stimulating OTA-induced PMK proliferation and hyperplasia. Implications. EGFR-mediated pathways were also responsible for tumor promotion due to OTA.
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Mehraj U, Ganai RA, Macha MA, Hamid A, Zargar MA, Bhat AA, Nasser MW, Haris M, Batra SK, Alshehri B, Al-Baradie RS, Mir MA, Wani NA. The tumor microenvironment as driver of stemness and therapeutic resistance in breast cancer: New challenges and therapeutic opportunities. Cell Oncol (Dordr) 2021; 44:1209-1229. [PMID: 34528143 DOI: 10.1007/s13402-021-00634-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2021] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Breast cancer (BC), the second most common cause of cancer-related deaths, remains a significant threat to the health and wellness of women worldwide. The tumor microenvironment (TME), comprising cellular components, such as cancer-associated fibroblasts (CAFs), immune cells, endothelial cells and adipocytes, and noncellular components such as extracellular matrix (ECM), has been recognized as a critical contributor to the development and progression of BC. The interplay between TME components and cancer cells promotes phenotypic heterogeneity, cell plasticity and cancer cell stemness that impart tumor dormancy, enhanced invasion and metastasis, and the development of therapeutic resistance. While most previous studies have focused on targeting cancer cells with a dismal prognosis, novel therapies targeting stromal components are currently being evaluated in preclinical and clinical studies, and are already showing improved efficacies. As such, they may offer better means to eliminate the disease effectively. CONCLUSIONS In this review, we focus on the evolving concept of the TME as a key player regulating tumor growth, metastasis, stemness, and the development of therapeutic resistance. Despite significant advances over the last decade, several clinical trials focusing on the TME have failed to demonstrate promising effectiveness in cancer patients. To expedite clinical efficacy of TME-directed therapies, a deeper understanding of the TME is of utmost importance. Secondly, the efficacy of TME-directed therapies when used alone or in combination with chemo- or radiotherapy, and the tumor stage needs to be studied. Likewise, identifying molecular signatures and biomarkers indicating the type of TME will help in determining precise TME-directed therapies.
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Affiliation(s)
- Umar Mehraj
- Department of Bioresources, University of Kashmir, Srinagar, Jammu & Kashmir, India
| | - Rais A Ganai
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science & Technology , Awantipora, Jammu & Kashmir, India
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science & Technology , Awantipora, Jammu & Kashmir, India
| | - Abid Hamid
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Mohammed A Zargar
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Ajaz A Bhat
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Mohd Wasim Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Mohammad Haris
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar.,Laboratory of Animal Research, Qatar University, Doha, Qatar
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska, Lincoln, NE, USA.,Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Bader Alshehri
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Almajmaah, Kingdom of Saudi Arabia
| | - Raid Saleem Al-Baradie
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Almajmaah, Kingdom of Saudi Arabia
| | - Manzoor A Mir
- Department of Bioresources, University of Kashmir, Srinagar, Jammu & Kashmir, India.
| | - Nissar Ahmad Wani
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India.
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Alonso-Diez Á, Cáceres S, Peña L, Crespo B, Illera JC. Anti-Angiogenic Treatments Interact with Steroid Secretion in Inflammatory Breast Cancer Triple Negative Cell Lines. Cancers (Basel) 2021; 13:3668. [PMID: 34359570 PMCID: PMC8345132 DOI: 10.3390/cancers13153668] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/13/2021] [Accepted: 07/16/2021] [Indexed: 12/21/2022] Open
Abstract
Human inflammatory breast cancer (IBC) is a highly angiogenic disease for which antiangiogenic therapy has demonstrated only a modest response, and the reason for this remains unknown. Thus, the purpose of this study was to determine the influence of different antiangiogenic therapies on in vitro and in vivo steroid hormone and angiogenic growth factor production using canine and human inflammatory breast carcinoma cell lines as well as the possible involvement of sex steroid hormones in angiogenesis. IPC-366 and SUM149 cell lines and xenotransplanted mice were treated with different concentrations of VEGF, SU5416, bevacizumab and celecoxib. Steroid hormone (progesterone, dehydroepiandrostenedione, androstenedione, testosterone, dihydrotestosterone, estrone sulphate and 17β-oestradiol), angiogenic growth factors (VEGF-A, VEGF-C and VEGF-D) and IL-8 determinations in culture media, tumour homogenate and serum samples were assayed by EIA. In vitro, progesterone- and 17β-oestradiol-induced VEGF production promoting cell proliferation and androgens are involved in the formation of vascular-like structures. In vivo, intratumoural testosterone concentrations were augmented and possibly associated with decreased metastatic rates, whereas elevated E1SO4 concentrations could promote tumour progression after antiangiogenic therapies. In conclusion, sex steroid hormones could regulate the production of angiogenic factors. The intratumoural measurement of sex steroids and growth factors may be useful to develop preventive and individualized therapeutic strategies.
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Affiliation(s)
- Ángela Alonso-Diez
- Department Animal Medicine, Surgery and Pathology, Veterinary Medicine School, Complutense University of Madrid (UCM), 28040 Madrid, Spain
| | - Sara Cáceres
- Department Animal Physiology, Veterinary Medicine School, Complutense University of Madrid (UCM), 28040 Madrid, Spain
| | - Laura Peña
- Department Animal Medicine, Surgery and Pathology, Veterinary Medicine School, Complutense University of Madrid (UCM), 28040 Madrid, Spain
| | - Belén Crespo
- Department Animal Physiology, Veterinary Medicine School, Complutense University of Madrid (UCM), 28040 Madrid, Spain
| | - Juan Carlos Illera
- Department Animal Physiology, Veterinary Medicine School, Complutense University of Madrid (UCM), 28040 Madrid, Spain
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Kaduševičius E. Novel Applications of NSAIDs: Insight and Future Perspectives in Cardiovascular, Neurodegenerative, Diabetes and Cancer Disease Therapy. Int J Mol Sci 2021; 22:6637. [PMID: 34205719 PMCID: PMC8235426 DOI: 10.3390/ijms22126637] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/28/2021] [Accepted: 06/01/2021] [Indexed: 01/22/2023] Open
Abstract
Once it became clear that inflammation takes place in the modulation of different degenerative disease including neurodegenerative, cardiovascular, diabetes and cancer the researchers has started intensive programs evaluating potential role of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention or therapy of these diseases. This review discusses the novel mechanism of action of NSAIDs and its potential use in the pharmacotherapy of neurodegenerative, cardiovascular, diabetes and cancer diseases. Many different molecular and cellular factors which are not yet fully understood play an important role in the pathogenesis of inflammation, axonal damage, demyelination, atherosclerosis, carcinogenesis thus further NSAID studies for a new potential indications based on precise pharmacotherapy model are warranted since NSAIDs are a heterogeneous group of medicines with relative different pharmacokinetics and pharmacodynamics profiles. Hopefully the new data from studies will fill in the gap between experimental and clinical results and translate our knowledge into successful disease therapy.
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Affiliation(s)
- Edmundas Kaduševičius
- Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, 9 A. Mickeviciaus Street, LT-44307 Kaunas, Lithuania
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27
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Prego-Domínguez J, Takkouche B. Paracetamol Intake and Hematologic Malignancies: A Meta-Analysis of Observational Studies. J Clin Med 2021; 10:jcm10112429. [PMID: 34070784 PMCID: PMC8198062 DOI: 10.3390/jcm10112429] [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: 03/29/2021] [Revised: 05/12/2021] [Accepted: 05/27/2021] [Indexed: 11/16/2022] Open
Abstract
Hematologic malignancies cause more than half a million deaths every year worldwide. Analgesics were suggested as chemopreventive agents for several cancers but so far, results from individual studies about the relationship between paracetamol (acetaminophen) use and hematologic malignancies are conflicting. Therefore, we decided to perform a systematic review and meta-analysis. We retrieved studies published in any language by systematically searching Medline, Embase, Conference Proceedings Citation Index, Open Access Theses and Dissertations, and the five regional bibliographic databases of the World Health Organization until December 2020. Pooled odds ratios (OR) and their 95% confidence intervals (CI) were calculated according to the inverse of their variances. We performed separate analyses by histologic type. We also evaluated publication bias and assessed quality. A total of 17 study units met our inclusion criteria. The results show an association of hematologic malignancies with any paracetamol intake (OR 1.49, 95% CI 1.23-1.80) and with high paracetamol intake (OR 1.77, 95% CI 1.45-2.16). By subtype, risk was higher for multiple myeloma (OR 2.13, 95% CI 1.54-2.94) for any use and OR 3.16, 95% CI 1.96-5.10 for high intake, while risk was lower and non-significant for non-Hodgkin lymphoma. This meta-analysis provides evidence that paracetamol intake may be associated with hematologic malignancies and suggests that a dose-response effect is plausible. These results are unlikely to be due to publication bias or low quality of studies. Future research should focus on assessing the dose-response relationship.
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Affiliation(s)
- Jesús Prego-Domínguez
- Department of Preventive Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain;
| | - Bahi Takkouche
- Department of Preventive Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain;
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBER-ESP), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-881-812268; Fax: +34-981-572282
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Gairola K, Gururani S, Bahuguna A, Garia V, Pujari R, Dubey SK. Natural products targeting cancer stem cells: Implications for cancer chemoprevention and therapeutics. J Food Biochem 2021; 45:e13772. [PMID: 34028051 DOI: 10.1111/jfbc.13772] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 04/06/2021] [Accepted: 05/03/2021] [Indexed: 12/14/2022]
Abstract
Cancer, being the leading cause of death in the globe, has been one of the major thrust areas of research worldwide. In a new paradigm about neoplastic transformations, the initiation and recurrence of disease is attributed to few mutated cells in bulk of tumor called cancer stem cells (CSCs). CSCs have capacity of self-renewal and differentiation, which are known for resistance to radio and chemotherapy leading to recurrence of the disease even after treatment. Most of traditional drugs implicated in cancer therapy targeting primary tumors have substantial toxicity to the physiological system and have not been efficient in targeting these CSCs leading to poor prognosis. Targeting these CSCs in bulk of tumor might be novel strategy for cancer chemoprevention and therapeutics. Diet-derived interventions and diverse natural products are known to target these CSCs and related signaling pathways, namely, Wnt, Notch, and Hedgehog pathways, which are implicated for CSC self-renewal. PRACTICAL APPLICATIONS: Cancer remains a global challenge even in this century. Poor prognosis, survival rate, and recurrence of the disease have been the major concerns in traditional cancer therapy regimes. Targeting cancer stem cells might be novel strategy for elimination and cure of the chronic disease as they are known to modulate all stages of carcinogenesis and responsible for recurrence and resistance to chemotherapy and radiotherapy. The evidence support that natural products might inhibit, delay, or reverse the process of tumorigenesis and modulate the different signaling pathways implicated for cancer stem cells self-renewal and differentiation. Natural products have minimal toxicity compared to traditional cancer therapy drugs since they have long been utilized in our food habits without any major side effects reported. Thus, targeting cancer stem cells with natural product might be a novel strategy for drug development in cancer chemoprevention and therapeutics.
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Affiliation(s)
- Kanchan Gairola
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Shriya Gururani
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Ananya Bahuguna
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Vaishali Garia
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Rohit Pujari
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Shiv K Dubey
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
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Tudor DV, Bâldea I, Olteanu DE, Fischer-Fodor E, Piroska V, Lupu M, Călinici T, Decea RM, Filip GA. Celecoxib as a Valuable Adjuvant in Cutaneous Melanoma Treated with Trametinib. Int J Mol Sci 2021; 22:4387. [PMID: 33922284 PMCID: PMC8122835 DOI: 10.3390/ijms22094387] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Melanoma patients stop responding to targeted therapies mainly due to mitogen activated protein kinase (MAPK) pathway re-activation, phosphoinositide 3 kinase/the mechanistic target of rapamycin (PI3K/mTOR) pathway activation or stromal cell influence. The future of melanoma treatment lies in combinational approaches. To address this, our in vitro study evaluated if lower concentrations of Celecoxib (IC50 in nM range) could still preserve the chemopreventive effect on melanoma cells treated with trametinib. MATERIALS AND METHODS All experiments were conducted on SK-MEL-28 human melanoma cells and BJ human fibroblasts, used as co-culture. Co-culture cells were subjected to a celecoxib and trametinib drug combination for 72 h. We focused on the evaluation of cell death mechanisms, melanogenesis, angiogenesis, inflammation and resistance pathways. RESULTS Low-dose celecoxib significantly enhanced the melanoma response to trametinib. The therapeutic combination reduced nuclear transcription factor (NF)-kB (p < 0.0001) and caspase-8/caspase-3 activation (p < 0.0001), inhibited microphthalmia transcription factor (MITF) and tyrosinase (p < 0.05) expression and strongly down-regulated the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway more significantly than the control or trametinib group (p < 0.0001). CONCLUSION Low concentrations of celecoxib (IC50 in nM range) sufficed to exert antineoplastic capabilities and enhanced the therapeutic response of metastatic melanoma treated with trametinib.
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Affiliation(s)
- Diana Valentina Tudor
- Department of Physiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.V.T.); (I.B.); (M.L.); (R.M.D.); (G.A.F.)
| | - Ioana Bâldea
- Department of Physiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.V.T.); (I.B.); (M.L.); (R.M.D.); (G.A.F.)
| | - Diana Elena Olteanu
- Department of Physiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.V.T.); (I.B.); (M.L.); (R.M.D.); (G.A.F.)
| | - Eva Fischer-Fodor
- “Prof. Dr. Ion Chiricuță” Oncology Institute, 400015 Cluj-Napoca, Romania; (E.F.-F.); (V.P.)
| | - Virag Piroska
- “Prof. Dr. Ion Chiricuță” Oncology Institute, 400015 Cluj-Napoca, Romania; (E.F.-F.); (V.P.)
| | - Mihai Lupu
- Department of Physiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.V.T.); (I.B.); (M.L.); (R.M.D.); (G.A.F.)
| | - Tudor Călinici
- Department of Medical Informatics and Biostatistics, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
| | - Roxana Maria Decea
- Department of Physiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.V.T.); (I.B.); (M.L.); (R.M.D.); (G.A.F.)
| | - Gabriela Adriana Filip
- Department of Physiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.V.T.); (I.B.); (M.L.); (R.M.D.); (G.A.F.)
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Eligini S, Colli S, Habib A, Aldini G, Altomare A, Banfi C. Cyclooxygenase-2 Glycosylation Is Affected by Peroxynitrite in Endothelial Cells: Impact on Enzyme Activity and Degradation. Antioxidants (Basel) 2021; 10:496. [PMID: 33806920 PMCID: PMC8005028 DOI: 10.3390/antiox10030496] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/15/2021] [Accepted: 03/19/2021] [Indexed: 12/12/2022] Open
Abstract
The exposure of human endothelial cells to 3-morpholinosydnonimine (SIN-1) induced the expression of cyclooxygenase-2 (COX-2) in a dose- and time-dependent manner. Interestingly, after a prolonged incubation (>8 h) several proteoforms were visualized by Western blot, corresponding to different states of glycosylation of the protein. This effect was specific for SIN-1 that generates peroxynitrite and it was not detected with other nitric oxide-donors. Metabolic labeling experiments using 35S or cycloheximide suggested that the formation of hypoglycosylated COX-2 was dependent on de novo synthesis of the protein rather than the deglycosylation of the native protein. Moreover, SIN-1 reduced the activity of the hexokinase, the enzyme responsible for the first step of glycolysis. The hypoglycosylated COX-2 induced by SIN-1 showed a reduced capacity to generate prostaglandins and the activity was only partially recovered after immunoprecipitation. Finally, hypoglycosylated COX-2 showed a more rapid rate of degradation compared to COX-2 induced by IL-1α and an alteration in the localization with an accumulation mainly detected in the nuclear membrane. Our results have important implication to understand the effect of peroxynitrite on COX-2 expression and activity, and they may help to identify new pharmacological tools direct to increase COX-2 degradation or to inhibit its activity.
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Affiliation(s)
- Sonia Eligini
- Centro Cardiologico Monzino I.R.C.C.S., 20138 Milan, Italy;
| | - Susanna Colli
- Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, 20133 Milan, Italy;
| | - Aida Habib
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon;
- INSERM-UMR1149, Centre de Recherche sur l’Inflammation, and Sorbonne Paris Cité, Laboratoire d’Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Université de Paris, 75018 Paris, France
| | - Giancarlo Aldini
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, 20133 Milano, Italy; (G.A.); (A.A.)
| | - Alessandra Altomare
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, 20133 Milano, Italy; (G.A.); (A.A.)
| | - Cristina Banfi
- Centro Cardiologico Monzino I.R.C.C.S., 20138 Milan, Italy;
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Tabana Y, Okoye IS, Siraki A, Elahi S, Barakat KH. Tackling Immune Targets for Breast Cancer: Beyond PD-1/PD-L1 Axis. Front Oncol 2021; 11:628138. [PMID: 33747948 PMCID: PMC7973280 DOI: 10.3389/fonc.2021.628138] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 02/08/2021] [Indexed: 12/24/2022] Open
Abstract
The burden of breast cancer is imposing a huge global problem. Drug discovery research and novel approaches to treat breast cancer have been carried out extensively over the last decades. Although immune checkpoint inhibitors are showing promising preclinical and clinical results in treating breast cancer, they are facing multiple limitations. From an immunological perspective, a recent report highlighted breast cancer as an "inflamed tumor" with an immunosuppressive microenvironment. Consequently, researchers have been focusing on identifying novel immunological targets that can tune up the tumor immune microenvironment. In this context, several novel non-classical immune targets have been targeted to determine their ability to uncouple immunoregulatory pathways at play in the tumor microenvironment. This article will highlight strategies designed to increase the immunogenicity of the breast tumor microenvironment. It also addresses the latest studies on targets which can enhance immune responses to breast cancer and discusses examples of preclinical and clinical trial landscapes that utilize these targets.
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Affiliation(s)
- Yasser Tabana
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Isobel S. Okoye
- School of Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Arno Siraki
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Shokrollah Elahi
- School of Dentistry, University of Alberta, Edmonton, AB, Canada
- Department of Oncology, University of Alberta, Edmonton, AB, Canada
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
| | - Khaled H. Barakat
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
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Monteleone NJ, Lutz CS. miR-708-5p enhances erlotinib/paclitaxel efficacy and overcomes chemoresistance in lung cancer cells. Oncotarget 2020; 11:4699-4721. [PMID: 33473256 PMCID: PMC7771713 DOI: 10.18632/oncotarget.27840] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 11/23/2020] [Indexed: 12/16/2022] Open
Abstract
Lung cancer is a collection of aggressive tumors generally not diagnosed until late-stage, resulting in high mortality rates. The vast majority of non-small cell lung cancer (NSCLC) patients undergo combinatory chemotherapeutic treatment, which initially reduces tumor growth, but frequently becomes ineffective due to toxicity and resistance. Researchers have identified multiple signaling pathways involved in lung cancer chemoresistance, including cyclooxygenase-2 (COX-2)/microsomal prostaglandin E synthase-1 (mPGES-1) derived prostaglandin E2 (PGE2). While COX-2 inhibitors have shown promise in the clinic, their use is limited due to severe side effects. One novel approach to effectively suppress COX-2 signaling is through microRNA (miRNA). MiRNAs are small-noncoding RNAs commonly misexpressed in cancer. One tumor suppressive miRNA, miR-708-5p, has been shown to repress pro-resistant signaling pathways, including COX-2 and mPGES-1. Here, we demonstrate that chemotherapies reduce COX-2 expression, possibly through induction of miR-708-5p. Moreover, combination treatment of erlotinib (ERL) or paclitaxel (PAC) with miR-708-5p enhances COX-2 and mPGES-1 protein suppression. We also show that combination chemotherapeutic and miR-708-5p treatment intensifies the anti-proliferative and pro-apoptotic effects of ERL and PAC. We also created ERL and PAC resistant lung cancer cell lines, which have increased COX-2 expression and diminished miR-708-5p levels compared to naïve lung cancer cells. While ERL and PAC treatments do not alter resistant cell phenotype alone, combination treatment with miR-708-5p partially restores the chemotherapies' anti-proliferative effects and fully restores their pro-apoptotic qualities. These data suggest miR-708-5p may have potential combinatory therapeutic value to more efficaciously treat lung tumors while overcoming chemoresistance.
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Affiliation(s)
- Nicholas J Monteleone
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical & Health Sciences, New Jersey Medical School, School of Graduate Studies, Newark, NJ 07103, USA
| | - Carol S Lutz
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical & Health Sciences, New Jersey Medical School, School of Graduate Studies, Newark, NJ 07103, USA
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Kaur J, Bhardwaj A, Wuest F. In Cellulo Generation of Fluorescent Probes for Live-Cell Imaging of Cylooxygenase-2. Chemistry 2020; 27:3326-3337. [PMID: 32786126 DOI: 10.1002/chem.202003315] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/09/2020] [Indexed: 02/01/2023]
Abstract
Live-cell imaging with fluorescent probes is an essential tool in chemical biology to visualize the dynamics of biological processes in real-time. Intracellular disease biomarker imaging remains a formidable challenge due to the intrinsic limitations of conventional fluorescent probes and the complex nature of cells. This work reports the in cellulo assembly of a fluorescent probe to image cyclooxygenase-2 (COX-2). We developed celecoxib-azide derivative 14, possessing favorable biophysical properties and excellent COX-2 selectivity profile. In cellulo strain-promoted fluorogenic click chemistry of COX-2-engaged compound 14 with non/weakly-fluorescent compounds 11 and 17 formed fluorescent probes 15 and 18 for the detection of COX-2 in living cells. Competitive binding studies, biophysical, and comprehensive computational analyses were used to describe protein-ligand interactions. The reported new chemical toolbox enables precise visualization and tracking of COX-2 in live cells with superior sensitivity in the visible range.
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Affiliation(s)
- Jatinder Kaur
- Department of Oncology, University of Alberta, Edmonton, AB, Canada.,Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Atul Bhardwaj
- Department of Oncology, University of Alberta, Edmonton, AB, Canada.,Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Frank Wuest
- Department of Oncology, University of Alberta, Edmonton, AB, Canada.,Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.,Department of Chemistry, University of Alberta, Edmonton, AB, Canada
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Sakamaki K, Watanabe K, Woo T, Masuda M. Multicentre randomised phase II study of the perioperative administration of flurbiprofen axetil in patients with non-small cell lung cancer: study protocol of the FLAX Study. BMJ Open 2020; 10:e040969. [PMID: 33257489 PMCID: PMC7705564 DOI: 10.1136/bmjopen-2020-040969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION In patients with non-small cell lung cancer, surgical treatment with postoperative adjuvant chemotherapy is performed. However, the improvement of overall survival achieved by postoperative adjuvant chemotherapy may be insufficient in consideration of the deterioration of quality of life (QOL). Considering the relationships among surgical treatments, inflammation and carcinogenesis, non-steroidal anti-inflammatory drugs (NSAIDs) are a candidate postoperative treatment for preventing recurrence and maintaining QOL. In this study, we investigate the effects of the perioperative administration of flurbiprofen axetil on postoperative recurrence in patients with non-small cell lung cancer. METHODS AND ANALYSIS This study is a multicentre, parallel group, open label, randomised controlled trial. Patients clinically suspected of non-small cell lung cancer are randomly assigned to the flurbiprofen axetil group or the no-NSAIDs group. A total of 420 patients (210 per group) will be registered. The primary analysis will evaluate the treatment effect of flurbiprofen axetil on postoperative recurrence. ETHICS AND DISSEMINATION The study protocol was approved by the Clinical Research Review Board of Saitama Medical University in September 2019 (No. 192002) and will be approved by each institutional review board of all participating institutions before patient enrolment. This study complies with the latest version of the Declaration of Helsinki, Clinical Trial Act and related notifications. Results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER Japan Registry of Clinical Trials (jRCTs031190167; Pre-results) (https://jrct.niph.go.jp/).
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Affiliation(s)
- Kentaro Sakamaki
- Center for Data Science, Yokohama City University, Yokohama, Japan
| | - Katsuya Watanabe
- General Thoracic Surgery, National Hospital Organisation Yokohama Medical Center, Yokohama, Japan
| | - Tetsukan Woo
- Respiratory Center, Yokohama City University Medical Center, Yokohama, Japan
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Leuti A, Fazio D, Fava M, Piccoli A, Oddi S, Maccarrone M. Bioactive lipids, inflammation and chronic diseases. Adv Drug Deliv Rev 2020; 159:133-169. [PMID: 32628989 DOI: 10.1016/j.addr.2020.06.028] [Citation(s) in RCA: 204] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 06/09/2020] [Accepted: 06/25/2020] [Indexed: 02/08/2023]
Abstract
Endogenous bioactive lipids are part of a complex network that modulates a plethora of cellular and molecular processes involved in health and disease, of which inflammation represents one of the most prominent examples. Inflammation serves as a well-conserved defence mechanism, triggered in the event of chemical, mechanical or microbial damage, that is meant to eradicate the source of damage and restore tissue function. However, excessive inflammatory signals, or impairment of pro-resolving/anti-inflammatory pathways leads to chronic inflammation, which is a hallmark of chronic pathologies. All main classes of endogenous bioactive lipids - namely eicosanoids, specialized pro-resolving lipid mediators, lysoglycerophopsholipids and endocannabinoids - have been consistently involved in the chronic inflammation that characterises pathologies such as cancer, diabetes, atherosclerosis, asthma, as well as autoimmune and neurodegenerative disorders and inflammatory bowel diseases. This review gathers the current knowledge concerning the involvement of endogenous bioactive lipids in the pathogenic processes of chronic inflammatory pathologies.
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Monteleone NJ, Lutz CS. miR-708-5p targets oncogenic prostaglandin E2 production to suppress a pro-tumorigenic phenotype in lung cancer cells. Oncotarget 2020; 11:2464-2483. [PMID: 32655834 PMCID: PMC7335672 DOI: 10.18632/oncotarget.27614] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 05/14/2020] [Indexed: 12/13/2022] Open
Abstract
Many cancers maintain an inflammatory microenvironment to promote their growth. Lung cancer is of particular importance, as it is the deadliest cancer worldwide. One inflammatory pathway commonly dysregulated in cancer is the metabolism of arachidonic acid (AA) by Cyclooxygenase-2 (COX-2) and microsomal Prostaglandin E Synthase 1 (mPGES-1) into Prostaglandin E2 (PGE2). While researchers have identified PGE2's pro-tumorigenic functions, the mechanisms governing overexpression of COX-2 and mPGES-1 are incompletely understood. MicroRNAs (miRNAs) are important post-transcriptional regulators commonly dysregulated in cancer. Interestingly, miR-708-5p (miR-708) is predicted to target both COX-2 and mPGES-1. In this study, we show that high miR-708 expression is associated with survival rates in lung squamous cell carcinoma patients. miR-708 also represses PGE2 production by suppressing both COX-2 and mPGES-1 expression in lung cancer cells. miR-708 regulation of COX-2 and mPGES-1 is mediated through targeting of their 3' untranslated regions (UTRs). Moreover, miR-708 decreases proliferation, survival, and migration of lung cancer cells, which can be partially attributed to miR-708's inhibition of PGE2 signaling. Lastly, we identify novel miR-708 predicted targets and possible regulators of miR-708 expression in lung cancer. Collectively, these data demonstrate that dysregulated miR-708 expression contributes to exacerbated PGE2 production, leading to an enhanced pro-tumorigenic phenotype in lung cancer cells.
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Affiliation(s)
- Nicholas J. Monteleone
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical & Health Sciences, New Jersey Medical School, School of Graduate Studies, Newark, NJ 07103, USA
| | - Carol S. Lutz
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical & Health Sciences, New Jersey Medical School, School of Graduate Studies, Newark, NJ 07103, USA
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Li S, Jiang M, Wang L, Yu S. Combined chemotherapy with cyclooxygenase-2 (COX-2) inhibitors in treating human cancers: Recent advancement. Biomed Pharmacother 2020; 129:110389. [PMID: 32540642 DOI: 10.1016/j.biopha.2020.110389] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 05/28/2020] [Accepted: 06/07/2020] [Indexed: 12/20/2022] Open
Abstract
Chemotherapy with a single chemotherapeutic agent or a combined chemotherapeutic regimen is the clinically standardized treatment for almost all human cancers. Upregulated expression of cyclooxygenase (COX)-2, also known as prostaglandin-endoperoxide synthase (PTGS), is associated with human carcinogenesis and cancer progression and COX-2 inhibitors show antitumor activity in different human cancers. Thus, a combination of chemotherapeutic agents with COX-2 inhibitors has been shown to improve therapeutic effects on human cancers. This review discusses and summarizes recent advances in cancer control and treatment using various antineoplastic drugs combined with COX-2 inhibitors. These combinations showed synergistic antitumor effects. At the gene level, COX-2 inhibitors can reduce inflammatory factors thereby regulating macrophage recruitment for activating the antitumor immune microenvironment; downregulating vascular endothelial growth factor (VEGF) to inhibit tumor angiogenesis; and inhibiting the PI3K/Akt signaling pathway to induce tumor cell apoptosis. In addition, such a combination can reduce toxicity and chemoresistance and enhance radiosensitivity, although COX-2 inhibitors-related cardiotoxicity may potentially affect its use. Further in-depth investigation of these drug combinations is needed to maximize antitumor efficacy and minimize the side effects.
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Affiliation(s)
- Shuangshuang Li
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Min Jiang
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Lu Wang
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Pharmacy, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250013, China.
| | - Shuwen Yu
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Pharmacy, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250013, China.
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Integrin αvβ3 in the Mediating Effects of Dihydrotestosterone and Resveratrol on Breast Cancer Cell Proliferation. Int J Mol Sci 2020; 21:ijms21082906. [PMID: 32326308 PMCID: PMC7216104 DOI: 10.3390/ijms21082906] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/16/2020] [Accepted: 04/17/2020] [Indexed: 12/16/2022] Open
Abstract
Hormones and their receptors play an important role in the development and progression of breast cancer. Hormones regulate the proliferation of breast cancer cells through binding between estrogen or progestins and steroid receptors that may reside in the cytoplasm or be transcriptionally activated as steroid–protein nuclear receptor complexes. However, receptors for nonpeptide hormones also exist in the plasma membrane. Via those receptors, hormones are able to stimulate breast cancer cell proliferation when activated. Integrins are heterodimeric structural proteins of the plasma membrane. Their primary functions are to interact with extracellular matrix proteins and growth factors. Recently, integrin αvβ3 has been identified as a receptor for nonpeptide hormones, such as thyroid hormone and dihydrotestosterone (DHT). DHT promotes the proliferation of human breast cancer cells through binding to integrin αvβ3. A receptor for resveratrol, a polyphenol stilbene, also exists on this integrin in breast cancer cells, mediating the anti-proliferative, pro-apoptotic action of the compound in these cells. Unrelated activities of DHT and resveratrol that originate at integrin depend upon downstream stimulation of mitogen-activated protein kinase (MAPK, ERK1/2) activity, suggesting the existence of distinct, function-specific pools of ERK1/2 within the cell. This review will discuss the features of these receptors in breast cancer cells, in turn suggesting clinical applications that are based on the interactions of resveratrol/DHT with integrin αvβ3 and other androgen receptors.
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Cyclooxygenase-2 as a Biomarker with Diagnostic, Therapeutic, Prognostic, and Predictive Relevance in Small Animal Oncology. J Vet Res 2020; 64:151-160. [PMID: 32258812 PMCID: PMC7105978 DOI: 10.2478/jvetres-2020-0018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 02/25/2020] [Indexed: 12/31/2022] Open
Abstract
In canine and feline populations, the number of neoplasm cases continues to increase around the world. Attempts are being made in centres of research to identify new biomarkers that speed up and improve the quality of oncological diagnostics and therapy in human and animal tumour patients. Cyclooxygenase-2 (COX-2) is a promising biomarker with increasing relevance to human oncology, but as yet with less application in veterinary oncology. The expression of COX-2 increases significantly during pathological processes involving inflammation, pain or fever. It is also overexpressed in humans presenting various types of tumours and in selected types of tumours in animals, particularly in dogs. This article discusses the expression of COX-2 in canine and feline tumours, the importance of COX-2 as a biomarker with diagnostic, therapeutic, prognostic and predictive relevance in oncology, and the clinical significance of inhibiting COX-2 overexpression in tumours.
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Saliakoura M, Reynoso-Moreno I, Pozzato C, Rossi Sebastiano M, Galié M, Gertsch J, Konstantinidou G. The ACSL3-LPIAT1 signaling drives prostaglandin synthesis in non-small cell lung cancer. Oncogene 2020; 39:2948-2960. [PMID: 32034305 PMCID: PMC7118021 DOI: 10.1038/s41388-020-1196-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 01/16/2020] [Accepted: 01/27/2020] [Indexed: 11/17/2022]
Abstract
Enhanced prostaglandin production promotes the development and progression of cancer. Prostaglandins are generated from arachidonic acid (AA) by the action of cyclooxygenase (COX) isoenzymes. However, how cancer cells are able to maintain an elevated supply of AA for prostaglandin production remains unclear. Here, by using lung cancer cell lines and clinically relevant KrasG12D-driven mouse models, we show that the long-chain acyl-CoA synthetase (ACSL3) channels AA into phosphatidylinositols to provide the lysophosphatidylinositol-acyltransferase 1 (LPIAT1) with a pool of AA to sustain high prostaglandin synthesis. LPIAT1 knockdown suppresses proliferation and anchorage-independent growth of lung cancer cell lines, and hinders in vivo tumorigenesis. In primary human lung tumors, the expression of LPIAT1 is elevated compared with healthy tissue, and predicts poor patient survival. This study uncovers the ACSL3-LPIAT1 axis as a requirement for the sustained prostaglandin synthesis in lung cancer with potential therapeutic value.
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Affiliation(s)
- Maria Saliakoura
- Institute of Pharmacology, University of Bern, 3010, Bern, Switzerland
| | - Inés Reynoso-Moreno
- Institute of Biochemistry and Molecular Medicine, University of Bern, 3012, Bern, Switzerland
| | - Chiara Pozzato
- Institute of Pharmacology, University of Bern, 3010, Bern, Switzerland
| | | | - Mirco Galié
- Department of Neuroscience, Biomedicine and Movement, University of Verona, 37134, Verona, Italy
| | - Jürg Gertsch
- Institute of Biochemistry and Molecular Medicine, University of Bern, 3012, Bern, Switzerland
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Arefi H, Naderi N, Shemirani ABI, Kiani Falavarjani M, Azami Movahed M, Zarghi A. Design, synthesis, and biological evaluation of new 1,4-diarylazetidin-2-one derivatives (β-lactams) as selective cyclooxygenase-2 inhibitors. Arch Pharm (Weinheim) 2020; 353:e1900293. [PMID: 31917485 DOI: 10.1002/ardp.201900293] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 12/14/2019] [Accepted: 12/17/2019] [Indexed: 11/07/2022]
Abstract
A new series of 1,4-diarylazetidin-2-one derivatives (β-lactams) were designed and synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of the COX-2 isozyme with IC50 values in the 0.05-0.11 µM range, and COX-2 selectivity indexes in the range of 170-703.7. Among the synthesized β-lactams, 3-methoxy-4-(4-(methylsulfonyl)phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (4j) possessing trimethoxy groups at the N-1 phenyl ring exhibited the highest COX-2 inhibitory selectivity and potency, even more potent than the reference drug celecoxib. The analgesic activity of the synthesized compounds was also determined using the formalin test. Compound 4f displayed the best analgesic activity among the synthesized molecules. Molecular modeling studies indicated that the methylsulfonyl pharmacophore group can be inserted into the secondary pocket of the COX-2 active site for interactions with Arg513 . The structure-activity data acquired indicate that the β-lactam ring moiety constitutes a suitable scaffold to design new 1,4-diarylazetidin-2-ones with selective COX-2 inhibitory activity.
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Affiliation(s)
- Hadi Arefi
- Department of Pharmaceutical Chemistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nima Naderi
- Department of Pharmacology and Toxicology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir B Irani Shemirani
- Student Research Committee, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mina Kiani Falavarjani
- Student Research Committee, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahsa Azami Movahed
- Department of Pharmaceutical Chemistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afshin Zarghi
- Department of Pharmaceutical Chemistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Sheng J, Sun H, Yu FB, Li B, Zhang Y, Zhu YT. The Role of Cyclooxygenase-2 in Colorectal Cancer. Int J Med Sci 2020; 17:1095-1101. [PMID: 32410839 PMCID: PMC7211146 DOI: 10.7150/ijms.44439] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 04/14/2020] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer is the third common cancer in this world, accounting for more than 1 million cases each year. However, detailed etiology and mechanism of colorectal cancer have not been fully understood. For example, cyclooxygenase-2 (COX-2) and its product prostaglandin E2 (PGE2) have been closely linked to its occurrence, progression and prognosis. However, the mechanisms on how COX-2 and PGE2-mediate the pathogenesis of colorectal cancer are obscure. In this review, we have summarized recent advances in studies of pathogenesis and control in colorectal cancer to assist further advances in the research for the cure of the cancer. In addition, the knowledge gained may also guide the audiences for reduction of the risk and control of this deadly disease.
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Affiliation(s)
- Juan Sheng
- Department of Gastroenterology, the Second People's Hospital of Yunnan Province, Kunming, Yunnan 650021, China
| | - Hong Sun
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Fu-Bing Yu
- Department of Gastroenterology, the Second People's Hospital of Yunnan Province, Kunming, Yunnan 650021, China
| | - Bo Li
- Department of General Surgery, The Second People's Hospital of Yunnan Province, Kunming, Yunnan 650021, China
| | - Yuan Zhang
- Tissue Tech Inc, Miami, Florida 33032, USA
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Cho KS, Sohn W, Lee YC, Chi SA, Cho JY, Kim K, Paik YH. Use of cyclooxygenase inhibitor and the risk of hepatocellular carcinoma in patients with chronic hepatitis B: A nested case-control study using a nationwide population-based data. J Viral Hepat 2020; 27:68-73. [PMID: 31505085 DOI: 10.1111/jvh.13201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 07/22/2019] [Accepted: 08/12/2019] [Indexed: 02/04/2023]
Abstract
The study aimed to investigate the relationship between the use of COX inhibitors and the risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB) using a nationwide population-based data. A nested case-control study was conducted using the National Health Insurance Service-National Sample Cohort (NHIS-NSC) from 2002 to 2013 in Korea. We compared the use of COX inhibitors between HCC cases and matched controls by categorizing 5 groups according to the cumulative defined daily dose (cDDD, <28, 28-90, 91-180, 181-360, and >360) adjusting the use of antiviral agents. A total of 4980 patients with CHB were analysed as 996 HCC cases and 3984 matched controls. The number of COX inhibitor users (≥28 cDDD) was 358 patients (36%) and 1814 patients (45%) in the HCC group and control group, respectively. The use of COX inhibitors was significantly associated with a decreased risk of HCC development compared with nonusers (adjusted odds ratio [OR] 0.62, 95% confidence interval [CI] 0.52-0.73, P < .001). There was a dose-dependent inverse relationship between the use of COX inhibitors and the risk of HCC. The adjusted ORs were 0.75 (95% CI: 0.63-0.90), 0.41 (95% CI: 0.31-0.56), 0.38 (95% CI: 0.25-0.57) and 0.49 (95% CI: 0.31-0.79) for the 28-90, 91-180, 181-360 and >360 cDDDs, respectively (P < .01). In conclusion, the use of COX inhibitors was associated with a reduced risk of HCC in CHB. COX inhibitor may have a chemopreventive role in HCC development in patients with chronic liver disease.
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Affiliation(s)
- Kyoung Sun Cho
- Department of Digital Health, Samsung Advanced Institute for Health Science and Technology, Sunkyunkwan University, Seoul, Korea
| | - Won Sohn
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Korea
| | - Yeong Chan Lee
- Department of Digital Health, Samsung Advanced Institute for Health Science and Technology, Sunkyunkwan University, Seoul, Korea
| | - Sang Ah Chi
- Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sunkyunkwan University, Seoul, Korea
| | - Ju-Yeon Cho
- Division of Gastroenterology and Hepatology, Department of Medicine, Chosun University, Gwang-Ju, Korea
| | - Kyunga Kim
- Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sunkyunkwan University, Seoul, Korea.,Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Seoul, Korea
| | - Yong-Han Paik
- Department of Digital Health, Samsung Advanced Institute for Health Science and Technology, Sunkyunkwan University, Seoul, Korea.,Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sunkyunkwan University, Seoul, Korea.,Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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COX-2 Signaling in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1277:87-104. [PMID: 33119867 DOI: 10.1007/978-3-030-50224-9_6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Tumorigenesis is a multistep, complicated process, and many studies have been completed over the last few decades to elucidate this process. Increasingly, many studies have shifted focus toward the critical role of the tumor microenvironment (TME), which consists of cellular players, cell-cell communications, and extracellular matrix (ECM). In the TME, cyclooxygenase-2 (COX-2) has been found to be a key molecule mediating the microenvironment changes. COX-2 is an inducible form of the enzyme that converts arachidonic acid into the signal transduction molecules (thromboxanes and prostaglandins). COX-2 is frequently expressed in many types of cancers and has been closely linked to its occurrence, progression, and prognosis. For example, COX-2 has been shown to (1) regulate tumor cell growth, (2) promote tissue invasion and metastasis, (3) inhibit apoptosis, (4) suppress antitumor immunity, and (5) promote sustainable angiogenesis. In this chapter, we summarize recent advances of studies that have evaluated COX-2 signaling in TME.
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Gastroenteropancreatic neuroendocrine neoplasms and inflammation: A complex cross-talk with relevant clinical implications. Crit Rev Oncol Hematol 2019; 146:102840. [PMID: 31918344 DOI: 10.1016/j.critrevonc.2019.102840] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 11/21/2019] [Accepted: 11/23/2019] [Indexed: 02/07/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are a group of tumors originating from the neuroendocrine system. They mainly occur in the digestive system and the respiratory tract. It is well-know a strict interaction between neuroendocrine system and inflammation, which can play an important role in NEN carcinogenesis. Inflammatory mediators, which are produced by the tumor microenvironment, can favor cancer induction and progression, and can promote immune editing. On the other hand, a balanced immune system represents a relevant step in cancer prevention through the elimination of dysplastic and cancer cells. Therefore, an inflammatory response may be both pro- and anti-tumorigenic. In this review, we provide an overview concerning the complex interplay between inflammation and gastroenteropancreatic NENs, focusing on the tumorigenesis and clinical implications in these tumors.
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Olgen S, Kotra LP. Drug Repurposing in the Development of Anticancer Agents. Curr Med Chem 2019; 26:5410-5427. [PMID: 30009698 DOI: 10.2174/0929867325666180713155702] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 06/14/2018] [Accepted: 06/28/2018] [Indexed: 01/07/2023]
Abstract
BACKGROUND Research into repositioning known drugs to treat cancer other than the originally intended disease continues to grow and develop, encouraged in part, by several recent success stories. Many of the studies in this article are geared towards repurposing generic drugs because additional clinical trials are relatively easy to perform and the drug safety profiles have previously been established. OBJECTIVE This review provides an overview of anticancer drug development strategies which is one of the important areas of drug restructuring. METHODS Repurposed drugs for cancer treatments are classified by their pharmacological effects. The successes and failures of important repurposed drugs as anticancer agents are evaluated in this review. RESULTS AND CONCLUSION Drugs could have many off-target effects, and can be intelligently repurposed if the off-target effects can be employed for therapeutic purposes. In cancer, due to the heterogeneity of the disease, often targets are quite diverse, hence a number of already known drugs that interfere with these targets could be deployed or repurposed with appropriate research and development.
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Affiliation(s)
- Sureyya Olgen
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Biruni University, Istanbul, Turkey
| | - Lakshmi P Kotra
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S 3M2, Canada.,Center for Molecular Design and Preformulations, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, M5G 1L7 Canada.,Multi-Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, M5G 1L7 Canada
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Benelli R, Barboro P, Costa D, Astigiano S, Barbieri O, Capaia M, Poggi A, Ferrari N. Multifocal Signal Modulation Therapy by Celecoxib: A Strategy for Managing Castration-Resistant Prostate Cancer. Int J Mol Sci 2019; 20:6091. [PMID: 31816863 PMCID: PMC6929142 DOI: 10.3390/ijms20236091] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 11/28/2019] [Accepted: 11/29/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Prostate cancer (PCa) is a significant health concern throughout the world. Standard therapy for advanced disease consists of anti-androgens, however, almost all prostate tumors become castration resistant (CRPC). Progression from androgen-sensitive PCa to CRPC is promoted by inflammatory signaling through cyclooxygenase-2 (COX-2) expression and ErbB family receptors/AKT activation, compensating androgen receptor inactivity. METHODS Making use of CRPC cell lines, we investigated the effects of the anti-inflammatory drug celecoxib. Biochemical data obtained using immunoblotting, enzyme-linked immunosorbent assay (ELISA), invasion, and xenografts were further integrated by bioinformatic analyses. RESULTS Celecoxib reduced cell growth and induced apoptosis through AKT blockade, cleavage of poly (ADP-ribose) polymerase-1 (PARP-1), and proteasomal degradation of the anti-apoptotic protein Mcl-1. Epidermal growth factor receptor (EGFR), ErbB2, and ErbB3 degradation, and heterogeneous nuclear ribonucleoprotein K (hnRNP K) downregulation, further amplified the inhibition of androgen signaling. Celecoxib reduced the invasive phenotype of CRPC cells by modulating NF-κB activity and reduced tumor growth in mice xenografts when administered in association with the anti-EGFR receptor antibody cetuximab. Bioinformatic analyses on human prostate cancer datasets support the relevance of these pathways in PCa progression. CONCLUSIONS Signaling nodes at the intersection of pathways implicated in PCa progression are simultaneously modulated by celecoxib treatment. In combination therapies with cetuximab, celecoxib could represent a novel therapeutic strategy to curb signal transduction during CRPC progression.
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Affiliation(s)
- Roberto Benelli
- Immunology, IRCCS Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132 Genova, Italy;
| | - Paola Barboro
- Academic Unit of Medical Oncology, IRCCS Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132 Genova, Italy;
| | - Delfina Costa
- Molecular Oncology & Angiogenesis, IRCCS Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132 Genova, Italy; (D.C.); (A.P.); (N.F.)
| | - Simonetta Astigiano
- Immunology, IRCCS Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132 Genova, Italy;
| | - Ottavia Barbieri
- Department of Experimental Medicine (DIMES), University of Genova, Via L.B. Alberti, 16132 Genova, Italy;
| | - Matteo Capaia
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, Via Balbi 5, 16126 Genova, Italy;
| | - Alessandro Poggi
- Molecular Oncology & Angiogenesis, IRCCS Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132 Genova, Italy; (D.C.); (A.P.); (N.F.)
| | - Nicoletta Ferrari
- Molecular Oncology & Angiogenesis, IRCCS Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132 Genova, Italy; (D.C.); (A.P.); (N.F.)
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Ayiomamitis GD, Notas G, Vasilakaki T, Tsavari A, Vederaki S, Theodosopoulos T, Kouroumalis E, Zaravinos A. Understanding the Interplay between COX-2 and hTERT in Colorectal Cancer Using a Multi-Omics Analysis. Cancers (Basel) 2019; 11:1536. [PMID: 31614548 PMCID: PMC6827032 DOI: 10.3390/cancers11101536] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 09/07/2019] [Accepted: 10/08/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Cyclooxygenase 2 (COX-2) is involved in the initial steps of colorectal cancer (CRC) formation, playing a key role in the catalysis of arachidonic acid to prostaglandin E2 (PGE2). The human telomerase reverse transcriptase (hTERT or TERT) also plays an important role in colorectal cancer growth, conferring sustained cell proliferation and survival. Although hTERT induces COX-2 expression in gastric and cervical cancer, their interaction has not been investigated in the context of CRC. METHODS COX-2, PGE2 levels, and telomerase activity were evaluated by immunohistochemistry, ELISA, and TRAP assay in 49 colorectal cancer samples. PTGS1, PTGS2, PTGES3, TERT mRNA, and protein levels were investigated using RNA-seq and antibody-based protein profiling data from the TCGA and HPA projects. A multi-omics comparison was performed between PTGS2 and TERT, using RNAseq, DNA methylation, copy number variations (CNVs), single nucleotide polymorphisms (SNPs), and insertions/deletions (Indels) data. RESULTS COX-2 expression was positive in 40/49 CRCs, bearing cytoplasmic and heterogeneous staining, from moderate to high intensity. COX-2 staining was mainly detected in the stroma of the tumor cells and the adjacent normal tissues. PGE2 expression was lower in CRC compared to the adjacent normal tissue, and inversely correlated to telomerase activity in right colon cancers. COX-1 and COX-2 were anticorrelated with TERT. Isoform structural analysis revealed the most prevalent transcripts driving the differential expression of PTGS1, PTGS2, PTGES3, and TERT in CRC. COX-2 expression was significantly higher among B-Raf proto-oncogene, serine/threonine kinase, mutant (BRAFmut) tumors. Kirsten ras oncogene (KRAS) mutations did not affect COX-2 or TERT expression. The promoter regions of COX-2 and TERT were reversely methylated. CONCLUSIONS Our data support that COX-2 is involved in the early stages of colorectal cancer development, initially affecting the tumor's stromal microenvironment, and, subsequently, the epithelial cells. They also highlight an inverse correlation between COX-2 expression and telomerase activity in CRC, as well as differentially methylated patterns within the promoter regions of COX-2 and TERT.
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Affiliation(s)
- Georgios D Ayiomamitis
- Laboratory of Gastroenterology Research, University of Crete, School of Medicine, 71013 Heraklion, Greece.
- 1st Department of Surgery, Tzaneio General Hospital, 18536 Piraeus, Greece.
| | - George Notas
- Laboratory of Gastroenterology Research, University of Crete, School of Medicine, 71013 Heraklion, Greece.
- Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, 71013 Heraklion, Greece.
| | - Thivi Vasilakaki
- Department of Pathology, Tzaneio General Hospital, 18536 Piraeus, Greece.
| | - Aikaterini Tsavari
- Department of Pathology, Tzaneio General Hospital, 18536 Piraeus, Greece.
| | - Styliani Vederaki
- 1st Department of Surgery, Tzaneio General Hospital, 18536 Piraeus, Greece.
| | - Theodosis Theodosopoulos
- 2nd Department of Surgery, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece.
| | - Elias Kouroumalis
- Laboratory of Gastroenterology Research, University of Crete, School of Medicine, 71013 Heraklion, Greece.
- Department of Gastroenterology and Hepatology, University Hospital of Heraklion, 71013 Heraklion, Greece.
| | - Apostolos Zaravinos
- Department of Life Sciences European University Cyprus, Nicosia 1516, Cyprus.
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Czogalla B, Kuhn C, Heublein S, Schmöckel E, Mayr D, Kolben T, Trillsch F, Burges A, Mahner S, Jeschke U, Hester A. EP3 receptor is a prognostic factor in TA-MUC1-negative ovarian cancer. J Cancer Res Clin Oncol 2019; 145:2519-2527. [PMID: 31485769 DOI: 10.1007/s00432-019-03017-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 08/30/2019] [Indexed: 12/20/2022]
Abstract
PURPOSE Prostaglandin-mediated inflammatory reactions play a major role in different cancers. Recently, it has been observed that prostaglandin E2-receptor 3 (EP3) might be an independent prognostic factor for overall survival in cervical and endometrial cancer. The role of EP3 expression in ovarian cancer is currently unknown. METHODS EP3 expression was analyzed by immunohistochemistry in 156 patient samples using the IR-scoring system. Expression levels were correlated with clinical and pathological parameters and with overall survival (OS) to assess for prognostic relevance. Data analysis was performed using Spearman's correlations, Kruskal-Wallis test and Kaplan-Meier estimates. RESULTS EP3 expression was significantly higher in clear-cell carcinoma (p < 0.001) compared to the other histological subtypes. No further correlations with clinical parameters could be found. EP3 expression correlated significantly with FSH-receptor expression (p < 0.001), galectin-1 expression in the tumor (p = 0.012) and with cytoplasmatic TA-MUC1 expression (p = 0.001). None of these parameters showed significant correlation with OS. In the TA-MUC1 negative subgroup, EP3 negative patients showed significantly longer OS (median OS: 102 months vs. 34 months in EP3 positive patients, p = 0.035), while EP3 did not appear to have prognostic relevance in the TA-MUC1-positive subgroup. CONCLUSION The potential prognostic relevance of EP3 expression for OS in TA-MUC1 negative patients might reflect an interplay between the COX and the MUC1 pathway, as it has been shown that MUC1 could induce COX2 expression. Our findings support the importance of the prostanoid signaling in TA-MUC1 negative ovarian cancer; however, future studies are necessary to characterize specific pathways and possible interactions.
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Affiliation(s)
- Bastian Czogalla
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Christina Kuhn
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Sabine Heublein
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
- Department of Gynecology and Obstetrics, University of Heidelberg, 69120, Heidelberg, Germany
| | - Elisa Schmöckel
- Department of Pathology, Ludwig-Maximilians University of Munich, 81337, Munich, Germany
| | - Doris Mayr
- Department of Pathology, Ludwig-Maximilians University of Munich, 81337, Munich, Germany
| | - Thomas Kolben
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Fabian Trillsch
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Alexander Burges
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Sven Mahner
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Udo Jeschke
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.
| | - Anna Hester
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany
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