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Li H, Pu Z, Fang J. Effect of Metformin on vascular endothelial injury in patients with non-small cell lung cancer treated with chemotherapy combined with bevacizumab. Cancer Chemother Pharmacol 2025; 95:59. [PMID: 40522519 DOI: 10.1007/s00280-025-04780-x] [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: 12/25/2024] [Accepted: 05/12/2025] [Indexed: 06/18/2025]
Abstract
OBJECTIVE This paper aimed to unravel the effect of metformin on vascular endothelial injury in patients with non-small cell lung cancer (NSCLC) treated with chemotherapy combined with bevacizumab. METHODS We recruited 120 NSCLC patients and then classified into A and B groups (n = 60 cases). A group was treated with chemotherapy + bevacizumab + metformin, and B group was treated with chemotherapy + bevacizumab. The efficacy, pro-inflammatory factors, immune factors, and markers of vascular endothelial injury before and after treatment were compared between the two groups. The incidence of adverse reactions and prognostic 1-year survival status during the treatment period in both groups were counted. RESULTS Higher ORR and DCR were observed in Group A relative to Group B. TNF-α, IL-2, IL-12, ET-1, TM, and vWF were elevated in both groups after treatment, but were lower in Group A than in Group B. CD3+, CD4+, and CD4+/CD8+ were reduced in both groups after treatment, but were higher in Group A than in Group B. OS and DFS were higher in Group A than in Group B. CONCLUSION Metformin has some anti-inflammatory and immunoprotective effects on NSCLC patients treated with chemotherapy combined with bevacizumab, which may help to attenuate the vascular endothelial injury induced by chemotherapy and bevacizumab treatment and further improve the prognosis.
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Affiliation(s)
- Hongyan Li
- Department of Thoracic Surgery, Zhongda Hospital Southeast University, No.87 Dingjiaqiao, Gulou District, Nanjing, 210009, Jiangsu Province, China.
| | - Zhenye Pu
- Department of Thoracic Surgery, Zhongda Hospital Southeast University, No.87 Dingjiaqiao, Gulou District, Nanjing, 210009, Jiangsu Province, China
| | - Jin Fang
- Department of Thoracic Surgery, Zhongda Hospital Southeast University, No.87 Dingjiaqiao, Gulou District, Nanjing, 210009, Jiangsu Province, China
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Song Z, Wang Q, Xiong H, Xiao J, Zhou Z, Li T, Sun Q, Qiu L, Tan Y, Liu X, Jiang H, Han S, Wang X. Bionic gene delivery system activates tumor autophagy and immunosuppressive niche to sensitize anti-PD-1 treatment against STK11-mutated lung adenocarcinoma. J Nanobiotechnology 2025; 23:312. [PMID: 40275340 PMCID: PMC12020135 DOI: 10.1186/s12951-025-03404-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: 11/21/2024] [Accepted: 04/15/2025] [Indexed: 04/26/2025] Open
Abstract
Clinical data have shown that Serine/Threonine Kinase 11 (STK11) mutation may be associated with an immunosuppressive tumor microenvironment (ITEM) and poor prognosis and failure of anti-PD-1 (αPD1) treatment in non-small cell lung cancer (NSCLC). To explore the potential of restoring STK11 protein in immunotherapy, a bionic gene delivery system was prepared by coating the STK11-encoded DNA-cationic polymer complex core with the tumor cell membrane, termed STK11@PPCM. STK11@PPCM could specifically bind with NSCLC cells and achieve precise delivery of STK11-encoded DNA. The released DNA effectively restored the STK11 protein expression, consequently reactivating autophagy and immunogenic cell death (ICD) in cancer cells. The liberated damage-associated molecular patterns (DAMPs) and autophagosome induced dendritic cells (DCs) maturation, which in turn enhanced CD8 + T cell infiltration, M1 macrophage polarization, and proinflammatory factor expression, thereby reversing the ITEM. Moreover, STK11@PPCM was also found to improve the sensitivity of cancer cells to αPD1 by increasing the expression of PD-L1, which was confirmed in STK11-mutated NSCLC cell xenografted mouse models, constructed by CRISPR-Cas9 knockout technology. This work demonstrated for the first time that restoration of functional STK11 can effectively reverse ITME and boost αPD1 efficacy in NSCLC, offering a new therapeutic approach for STK11-mutated lung adenocarcinoma in clinic.
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Affiliation(s)
- Zhongquan Song
- Department of Pulmonary and Critical Care Medicine, Medical School, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Qikai Wang
- Health Management Center, Weifang People's Hospital, Shandong Second Medical University, Weifang, Shandong, 261000, China
| | - Hongjie Xiong
- State Key Laboratory of Digital Medical Engineering, National Demonstration Center for Experimental Biomedical Engineering Education, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, 210096, China
| | - Jiang Xiao
- State Key Laboratory of Digital Medical Engineering, National Demonstration Center for Experimental Biomedical Engineering Education, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, 210096, China
| | - Zihan Zhou
- Department of Pulmonary and Critical Care Medicine, Medical School, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Tianxiang Li
- Department of Pulmonary and Critical Care Medicine, Medical School, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Qian Sun
- Department of Pulmonary and Critical Care Medicine, Medical School, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Liping Qiu
- Department of Pulmonary and Critical Care Medicine, Medical School, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Yue Tan
- Department of Pulmonary and Critical Care Medicine, Medical School, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Xiaohui Liu
- State Key Laboratory of Digital Medical Engineering, National Demonstration Center for Experimental Biomedical Engineering Education, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, 210096, China.
| | - Hui Jiang
- State Key Laboratory of Digital Medical Engineering, National Demonstration Center for Experimental Biomedical Engineering Education, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, 210096, China.
| | - Shuhua Han
- Department of Pulmonary and Critical Care Medicine, Medical School, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, 210009, China.
| | - Xuemei Wang
- State Key Laboratory of Digital Medical Engineering, National Demonstration Center for Experimental Biomedical Engineering Education, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, 210096, China.
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Zhou H, Xiao J, Cheng Q, Wang W, Peng H, Lin X, Chen J, Wang X. Metformin inhibits migration and epithelial-to-mesenchymal transition in non-small cell lung cancer cells through AMPK-mediated GDF15 induction. Eur J Pharmacol 2024; 985:177127. [PMID: 39528101 DOI: 10.1016/j.ejphar.2024.177127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 10/06/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
The growth differentiation factor 15 (GDF15) may serve as a biomarker of metformin, which mediates the bodyweight lowering effect of metformin. However, whether GDF15 also serves as a molecular target of metformin to inhibit carcinogenesis remains largely unknown. This study examined the role and molecular mechanisms of GDF15 in the anticancer effects of metformin in non-small cell lung cancer (NSCLC) cells, which has never been reported before. We found that metformin significantly inhibited the migration of NSCLC A549 and NCI-H460 cells and reduced the expression of epithelial-to-mesenchymal transition (EMT)-related molecules, including neuro-cadherin (N-cadherin), matrix metalloproteinase 2 (MMP2), and the zinc finger transcription factor Snail, but increased epithelial cadherin (E-cadherin) expression. Furthermore, metformin increased GDF15 and its upstream transcription factors activated transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP) expressions and increased AMP-activated protein kinase (AMPK) phosphorylation in NSCLC cells. GDF15 siRNA partially reverses the inhibitory effect of metformin on NSCLC cell migration. Moreover, metformin-induced increases in GDF15, CHOP, and ATF4 expression and the inhibition of migration were partially reversed by treatment with Compound C, a specific AMPK inhibitor. Meanwhile, metformin significantly inhibited NCI-H460 xenograft tumor growth in nude mice, increased GDF15 expression, and regulated EMT- and migration-related protein expression in xenograft tumors. In conclusion, our results provide novel insights into revealing that GDF15 can serve as a potential molecular target of metformin owing to its anti-cancer effect in NSCLC, which is mediated by AMPK activation.
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Affiliation(s)
- Hongyu Zhou
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311400, China
| | - Jun Xiao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311400, China
| | - Qi Cheng
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311400, China
| | - Wen Wang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311400, China
| | - He Peng
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311400, China
| | - Xiaojian Lin
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311400, China
| | - Jiajun Chen
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311400, China
| | - Xingya Wang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311400, China.
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Martínez-Lira JL, Hernández-Gallegos E, DE Guadalupe Chávez-López M, Villalobos-Valencia R, Camacho J. The Effects of Nebivolol-Gefitinib-Loratadine Against Lung Cancer Cell Lines. In Vivo 2024; 38:2688-2695. [PMID: 39477390 PMCID: PMC11535926 DOI: 10.21873/invivo.13746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 09/03/2024] [Accepted: 09/04/2024] [Indexed: 11/07/2024]
Abstract
BACKGROUND/AIM Non-small-cell lung cancer (NSCLC) is the most frequently diagnosed malignancy and the first cause of cancer-related death. Thus, finding alternative therapeutic options is crucial. Drug repurposing offers therapeutic options in a simplified and affordable manner, especially to cancer patients in developing countries. Several drugs including antihistamines and beta-adrenergic receptor blockers (beta-blockers) display antiproliferative properties on cancer cells. Interestingly, NSCLC patients who had used either antihistamines or beta-blockers showed improved response to chemotherapy or reduced mortality in comparison to non-users of any of these drugs. However, combination therapy is gaining substantial interest in many cancers including non-EGFR mutated NSCLC. Here, we investigated the antineoplastic effect of the combination of the antihistamine loratadine, the beta-blocker nebivolol, and the tyrosine-kinase inhibitor gefitinib on NSCLC cell lines. MATERIALS AND METHODS A-549 and NCI-H1975 cell lines were used. The effect of nebivolol, gefitinib, and loratadine on the metabolic activity was studied using the MTT assay. The inhibitory concentrations (IC20 and IC50) were calculated and used in the drug-combination experiments. Apoptosis was investigated using flow cytometry; and cell survival using the colony formation assay. RESULTS The combination nebivolol-loratadine-gefitinib produced a significant synergistic effect on inhibiting the metabolic activity and colony formation, as well as on promoting apoptosis in both cell lines. Noteworthy, the effect on the cell line carrying the EGFR mutation (NCI-H1975) was very similar to the cell line that does not exhibit such mutation (A-549 cells). CONCLUSION The nebivolol-gefitinib-loratadine combination may be a promising alternative for lung cancer treatment.
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Affiliation(s)
- José Luis Martínez-Lira
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Ciudad de México, México
- UMAE, Hospital de Especialidades Nο. 25, Instituto Mexicano del Seguro Social, Monterrey Nuevo León, México
| | - Elisabeth Hernández-Gallegos
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Ciudad de México, México
| | - María DE Guadalupe Chávez-López
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Ciudad de México, México
| | - Ricardo Villalobos-Valencia
- Departamento de Oncología Médica, Hospital de Oncología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Javier Camacho
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Ciudad de México, México;
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Zhang Z, Zhao M, Wang Q, Wang X, Wang Y, Ge Y, Wu Z, Wang W, Shan L. Forkhead box protein FOXK1 disrupts the circadian rhythm to promote breast tumorigenesis in response to insulin resistance. Cancer Lett 2024; 599:217147. [PMID: 39094826 DOI: 10.1016/j.canlet.2024.217147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 06/09/2024] [Accepted: 07/27/2024] [Indexed: 08/04/2024]
Abstract
The dysregulation of circadian rhythm oscillation is a prominent feature of various solid tumors. Thus, clarifying the molecular mechanisms that maintain the circadian clock is important. In the present study, we revealed that the transcription factor forkhead box FOXK1 functions as an oncogene in breast cancer. We showed that FOXK1 recruits multiple transcription corepressor complexes, including NCoR/SMRT, SIN3A, NuRD, and REST/CoREST. Among them, the FOXK1/NCoR/SIN3A complex transcriptionally regulates a cohort of genes, including CLOCK, PER2, and CRY2, that are critically involved in the circadian rhythm. The complex promoted the proliferation of breast cancer cells by disturbing the circadian rhythm oscillation. Notably, the nuclear expression of FOXK1 was positively correlated with tumor grade. Insulin resistance gradually became more severe with tumor progression and was accompanied by the increased expression of OGT, which caused the nuclear translocation and increased expression of FOXK1. Additionally, we found that metformin downregulates FOXK1 and exports it from the nucleus, while HDAC inhibitors (HDACi) inhibit the FOXK1-related enzymatic activity. Combined treatment enhanced the expression of circadian clock genes through the regulation of FOXK1, thereby exerting an antitumor effect, indicating that highly nuclear FOXK1-expressing breast cancers are potential candidates for the combined application of metformin and HDACi.
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Affiliation(s)
- Zhaohan Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Minghui Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Qian Wang
- Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute, and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China; National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Xilin Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Yu Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Yuze Ge
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Zicheng Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Wenjuan Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Lin Shan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
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De-Leon-Covarrubias UE, Perez-Trujillo JJ, Villa-Cedillo SA, Martinez-Perez AG, Montes-de-Oca-Saucedo CR, Loera-Arias MDJ, Garcia-Garcia A, Saucedo-Cardenas O, Montes-de-Oca-Luna R. Unlocking the Potential: Caloric Restriction, Caloric Restriction Mimetics, and Their Impact on Cancer Prevention and Treatment. Metabolites 2024; 14:418. [PMID: 39195514 DOI: 10.3390/metabo14080418] [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: 06/25/2024] [Revised: 07/16/2024] [Accepted: 07/17/2024] [Indexed: 08/29/2024] Open
Abstract
Caloric restriction (CR) and its related alternatives have been shown to be the only interventions capable of extending lifespan and decreasing the risk of cancer, along with a reduction in burden in pre-clinical trials. Nevertheless, the results from clinical trials have not been as conclusive as the pre-clinical results. Recognizing the challenges associated with long-term fasting, the application of caloric restriction mimetics (CRMs), pharmacological agents that mimic the molecular effects of CR, to harness the potential benefits while overcoming the practical limitations of fasting has resulted in an interesting alternative. This review synthesizes the findings of diverse clinical trials evaluating the safety and efficacy of CR and CRMs. In dietary interventions, a fast-mimicking diet was the most tolerated to reduce tumoral growth markers and chemotherapy side effects. CRMs were well tolerated, and metformin and aspirin showed the most promising effect in reducing cancer risk in a selected group of patients. The application of CR and/or CRMs shows promising effects in anti-cancer therapy; however, there is a need for more evidence to safely include these interventions in standard-of-care therapies.
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Affiliation(s)
| | - Jose Juan Perez-Trujillo
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Sheila Adela Villa-Cedillo
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | | | | | - Maria de Jesus Loera-Arias
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Aracely Garcia-Garcia
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Odila Saucedo-Cardenas
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Roberto Montes-de-Oca-Luna
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
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Pujalte‐Martin M, Belaïd A, Bost S, Kahi M, Peraldi P, Rouleau M, Mazure NM, Bost F. Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759. Mol Oncol 2024; 18:1719-1738. [PMID: 38214418 PMCID: PMC11223609 DOI: 10.1002/1878-0261.13583] [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: 08/16/2023] [Revised: 11/15/2023] [Accepted: 12/29/2023] [Indexed: 01/13/2024] Open
Abstract
Metformin and IACS-010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS-010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS-01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS-01075.
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Affiliation(s)
- Marc Pujalte‐Martin
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Amine Belaïd
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Simon Bost
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Michel Kahi
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Pascal Peraldi
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Matthieu Rouleau
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
- CNRS UMR7370, LP2MNiceFrance
| | - Nathalie M. Mazure
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Frédéric Bost
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
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Kawakita E, Kanasaki K. Cancer biology in diabetes update: Focusing on antidiabetic drugs. J Diabetes Investig 2024; 15:525-540. [PMID: 38456597 PMCID: PMC11060166 DOI: 10.1111/jdi.14152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/25/2023] [Accepted: 01/08/2024] [Indexed: 03/09/2024] Open
Abstract
The association of type 2 diabetes with certain cancer risk has been of great interest for years. However, the effect of diabetic medications on cancer development is not fully understood. Prospective clinical trials have not elucidated the long-term influence of hypoglycemic drugs on cancer incidence and the safety for cancer-bearing patients with diabetes, whereas numerous preclinical studies have shown that antidiabetic drugs could have an impact on carcinogenesis processes beyond the glycemic control effect. Because there is no evidence of the safety profile of antidiabetic agents on cancer biology, careful consideration would be required when prescribing any medicines to patients with diabetes and existing tumor. In this review, we discuss the potential influence of each diabetes therapy in cancer 'initiation', 'promotion' and 'progression'.
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Affiliation(s)
- Emi Kawakita
- Department of Internal Medicine 1, Faculty of MedicineShimane UniversityIzumoJapan
| | - Keizo Kanasaki
- Department of Internal Medicine 1, Faculty of MedicineShimane UniversityIzumoJapan
- The Center for Integrated Kidney Research and Advance, Faculty of MedicineShimane UniversityIzumoJapan
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9
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Benjamin DJ, Haslam A, Prasad V. Cardiovascular/anti-inflammatory drugs repurposed for treating or preventing cancer: A systematic review and meta-analysis of randomized trials. Cancer Med 2024; 13:e7049. [PMID: 38491813 PMCID: PMC10943275 DOI: 10.1002/cam4.7049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 01/09/2024] [Accepted: 02/08/2024] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Due to encouraging pre-clinical data and supportive observational studies, there has been growing interest in applying cardiovascular drugs (including aspirin, angiotensin-converting enzyme [ACE] inhibitors, statins, and metformin) approved to treat diseases such as hypertension, hyperlipidemia, and diabetes mellitus to the field of oncology. Moreover, given growing costs with cancer care, these medications have offered a potentially more affordable avenue to treat or prevent recurrence of cancer. We sought to investigate the anti-cancer effects of drugs repurposed from cardiology or anti-inflammatories to treat cancer. We specifically evaluated the following drug classes: HMG-CoA reductase inhibitors (statins), cyclo-oxygenase inhibitors, aspirin, metformin, and both angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors. We also included non-steroidal anti-inflammatory drugs (NSAIDs) because they exert a similar mechanism to aspirin by blocking prostaglandins and reducing inflammation that is thought to promote the development of cancer. METHODS We performed a systematic literature review using PubMed and Web of Science with search terms including "aspirin," "NSAID," "statin" (including specific statin drug names), "metformin," "ACE inhibitors," and "ARBs" (including specific anti-hypertensive drug names) in combination with "cancer." Searches were limited to human studies published between 2000 and 2023. MAIN OUTCOMES AND MEASURES The number and percentage of studies reported positive results and pooled estimates of overall survival, progression-free survival, response, and disease-free survival. RESULTS We reviewed 3094 titles and included 67 randomized clinical trials. The most common drugs that were tested were metformin (n = 21; 30.9%), celecoxib (n = 20; 29.4%), and simvastatin (n = 8; 11.8%). There was only one study that tested cardiac glycosides and none that studied ACE inhibitors. The most common tumor types were non-small-cell lung cancer (n = 19; 27.9%); breast (n = 8; 20.6%), colorectal (n = 7; 10.3%), and hepatocellular (n = 6; 8.8%). Most studies were conducted in a phase II trial (n = 38; 55.9%). Most studies were tested in metastatic cancers (n = 49; 72.1%) and in the first-line setting (n = 36; 521.9%). Four studies (5.9%) were stopped early because of difficulty with accrual. The majority of studies did not demonstrate an improvement in either progression-free survival (86.1% of studies testing progression-free survival) or in overall survival (94.3% of studies testing overall survival). Progression-free survival was improved in five studies (7.4%), and overall survival was improved in three studies (4.4%). Overall survival was significantly worse in two studies (3.8% of studies testing overall survival), and progression-free survival was worse in one study (2.8% of studies testing progression-free survival). CONCLUSIONS AND RELEVANCE Despite promising pre-clinical and population-based data, cardiovascular drugs and anti-inflammatory medications have overall not demonstrated benefit in the treatment or preventing recurrence of cancer. These findings may help guide future potential clinical trials involving these medications when applied in oncology.
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Affiliation(s)
| | - Alyson Haslam
- Department of Epidemiology and BiostatisticsUniversity of CaliforniaSan FranciscoCaliforniaUnited States
| | - Vinay Prasad
- Department of Epidemiology and BiostatisticsUniversity of CaliforniaSan FranciscoCaliforniaUnited States
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10
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Chen L, Yin Y, Liu C, Liu J, Zheng M, Tang Y, Yang Q, Liu J, Chen F, Liu L, Liu G. Metformin alleviates bevacizumab-induced vascular endothelial injury in mice through growth differentiation factor 15 upregulation. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:343-351. [PMID: 38333748 PMCID: PMC10849206 DOI: 10.22038/ijbms.2023.72759.15827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 11/18/2023] [Indexed: 02/10/2024]
Abstract
Objectives Bevacizumab is a commonly used anticancer drug in clinical practice, but it often leads to adverse reactions such as vascular endothelial damage, hypertension, arterial and venous thrombosis, and bleeding. This study investigated the protective effects of metformin against bevacizumab-induced vascular injury in a mouse model and examined the possible involvement of GDF15/PI3K/AKT/FOXO/PPARγ signaling in the effects. Materials and Methods C57 male mice were purchased. To investigate metformin, the mice were assigned to the saline, bevacizumab (15 mg every 3 days), metformin (1200 mg/day), and bevacizumab+metformin groups. To investigate GDF15, the mice were assigned to the siNC+bevacizumab, siNC+bevacizumab+metformin, siGDF15+bevacizumab, and siGDF15+bevacizumab+metformin groups. Histological staining was used to evaluate vascular injury. Flow cytometry was used to evaluate apoptosis. ELISA was used to measure plasma endothelial injury markers and proinflammatory cytokines. qRT-PCR and western blot were used to determine the expression of GDF15 and PI3K/AKT/FOXO/PPARγ in aortic tissues. Results Metformin alleviated bevacizumab-induced abdominal aortic injury, endothelial cell apoptosis, and systemic inflammation in mice (all P<0.05). Metformin up-regulated GDF15 expression and PI3K/AKT/FOXO/PPARγ signaling in the abdominal aorta of mice treated with bevacizumab (all P<0.05). siGDF15 abolished the vascular protective and anti-inflammatory effects of metformin (all P<0.05). siGDF15 suppressed PI3K/AKT/FOXO/PPARγ signaling in the abdominal aorta of mice treated with bevacizumab (all P<0.05). Conclusion Metformin attenuates bevacizumab-induced vascular endothelial injury, apoptosis, and systemic inflammation by activating GDF15/PI3K/AKT/FOXO/PPARγ signaling.
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Affiliation(s)
- Liqiang Chen
- Department of Cardiovascular, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- These authors contributed equally to this work
| | - Yajuan Yin
- Department of Cardiovascular, The First Hospital of Hebei Medical University, Shijiazhuang, China
- These authors contributed equally to this work
| | - Chunmiao Liu
- Department of Obstetrics,The Fourth Hospital of Shijiazhuang,Shijiazhuang, China
| | - Junying Liu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Mingqi Zheng
- Department of Cardiovascular, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yida Tang
- Department of Cardiology, Peking University Third Hospital, 49 Huayuanbei Road, Haidian District, Beijing 100191, China
| | - Qing Yang
- Department of Cardiology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China
| | - Jing Liu
- Department of Cardiovascular, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Fan Chen
- Department of Cardiovascular, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lanbo Liu
- Department of Cardiovascular, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Gang Liu
- Department of Cardiovascular, The First Hospital of Hebei Medical University, Shijiazhuang, China
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11
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Wu Z, Wang W, Wei L, Zhu S. Current status and frontier tracking of clinical trials on Metformin for cancer treatment. J Cancer Res Clin Oncol 2023; 149:16931-16946. [PMID: 37698682 DOI: 10.1007/s00432-023-05391-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 09/01/2023] [Indexed: 09/13/2023]
Abstract
PURPOSE Metformin has been used clinically for more than six decades. Over time, numerous remarkable effects of metformin beyond the clinic have been discovered and discussed. Metformin has been shown to have a favorable impact on cancer therapy in addition to its clinically recognized hypoglycemic effect. However, the antitumor efficacy of metformin in humans has not been clearly demonstrated yet. Hence, a systematic analysis of the existing trials is necessary. METHODS Here, we retrieved clinical trials from the Clinical Trials.gov database to overview the clinical development of metformin for the treatment of cancer, analyze existing clinical results, and summarize some promising applications for specific cancer therapies. RESULTS The potential application of metformin contains three directions: Firstly, improvement of metabolic factors associated with treatment effects, such as insulin resistance and peripheral neuropathy. Secondly, in combination with immune checkpoint blockade effects. Finally, use it for the endocrine treatment of hormone-dependent cancers. CONCLUSION Although the outcomes of metformin as a repurposed agent in some trials have been unsatisfactory, it still has the potential to be used in select cancer therapy settings.
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Affiliation(s)
- Zhipeng Wu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Wei Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Lengyun Wei
- School of Life Science, Anhui Medical University, Hefei, China.
| | - Shenglong Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China.
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12
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Khadka S, Lin YH, Ackroyd J, Chen YA, Sheng Y, Qian W, Guo S, Chen Y, Behr E, Barekatain Y, Uddin N, Arthur K, Yan V, Hsu WH, Chang Q, Poral A, Tran T, Chaurasia S, Georgiou DK, Asara JM, Barthel FP, Millward SW, DePinho RA, Muller FL. Anaplerotic nutrient stress drives synergy of angiogenesis inhibitors with therapeutics targeting tumor metabolism. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.07.539744. [PMID: 37214825 PMCID: PMC10197573 DOI: 10.1101/2023.05.07.539744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Tumor angiogenesis is a cancer hallmark, and its therapeutic inhibition has provided meaningful, albeit limited, clinical benefit. While anti-angiogenesis inhibitors deprive the tumor of oxygen and essential nutrients, cancer cells activate metabolic adaptations to diminish therapeutic response. Despite these adaptations, angiogenesis inhibition incurs extensive metabolic stress, prompting us to consider such metabolic stress as an induced vulnerability to therapies targeting cancer metabolism. Metabolomic profiling of angiogenesis-inhibited intracranial xenografts showed universal decrease in tricarboxylic acid cycle intermediates, corroborating a state of anaplerotic nutrient deficit or stress. Accordingly, we show strong synergy between angiogenesis inhibitors (Avastin, Tivozanib) and inhibitors of glycolysis or oxidative phosphorylation through exacerbation of anaplerotic nutrient stress in intracranial orthotopic xenografted gliomas. Our findings were recapitulated in GBM xenografts that do not have genetically predisposed metabolic vulnerabilities at baseline. Thus, our findings cement the central importance of the tricarboxylic acid cycle as the nexus of metabolic vulnerabilities and suggest clinical path hypothesis combining angiogenesis inhibitors with pharmacological cancer interventions targeting tumor metabolism for GBM tumors.
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Affiliation(s)
- Sunada Khadka
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- MD Anderson UT Health Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Yu-Hsi Lin
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jeffrey Ackroyd
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- MD Anderson UT Health Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Yi-An Chen
- Cancer and Cell Biology Division, The Translational Genomics Research Institute (TGen), Phoenix, AZ, USA
| | - Yanghui Sheng
- Crown Bioscience Inc., Suzhou Industrial Park, 218 Xinghu Rd, Jiangsu, China
| | - Wubin Qian
- Crown Bioscience Inc., Suzhou Industrial Park, 218 Xinghu Rd, Jiangsu, China
| | - Sheng Guo
- Crown Bioscience Inc., Suzhou Industrial Park, 218 Xinghu Rd, Jiangsu, China
| | - Yining Chen
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Eliot Behr
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yasaman Barekatain
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- MD Anderson UT Health Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Nasir Uddin
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kenisha Arthur
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Victoria Yan
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- MD Anderson UT Health Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Wen-Hao Hsu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Qing Chang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anton Poral
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Theresa Tran
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Surendra Chaurasia
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dimitra K Georgiou
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John M Asara
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Floris P Barthel
- Cancer and Cell Biology Division, The Translational Genomics Research Institute (TGen), Phoenix, AZ, USA
| | - Steve W Millward
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ronald A DePinho
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Florian L Muller
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- MD Anderson UT Health Graduate School of Biomedical Sciences, Houston, TX, USA
- Present address: Sporos Bioventures, Houston, TX, USA
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13
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Yang K, Lu HH, Zhao W, Zhao Q. Efficacy and safety of metformin in combination with chemotherapy in cancer patients without diabetes: systematic review and meta-analysis. Front Oncol 2023; 13:1176885. [PMID: 37546417 PMCID: PMC10402741 DOI: 10.3389/fonc.2023.1176885] [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: 03/01/2023] [Accepted: 06/26/2023] [Indexed: 08/08/2023] Open
Abstract
Background The results of a meta-analysis of retrospective studies suggest that the use of metformin in cancer patients may prolong progression-free disease survival and overall survival. However, the studies included in the meta-analysis did not strictly distinguish between patients with or without type 2 diabetes mellitus. Therefore, further studies are needed to assess whether the use of adjuvant chemotherapy with metformin in cancer patients without diabetes improves prognosis. Method Systematic searches of Embase, Pubmed, and The Cochrane library were performed for the subject terms metformin and neoplasm and for free words. Data related to PFS, OS were extracted according to inclusion exclusion criteria. The data were combined and meta-analysis was performed using Review Manager 5.4 to confirm the efficacy and safety of metformin administration. Results There were 3228 publications retrieved from the database and a total of 13 publications with 955 patients were included in the meta-analysis after screening. All included studies were randomised controlled trials. Metformin combined with adjuvant chemotherapy did not improve progression-free survival (HR=1,95CI 0.79-1.25), overall survival (HR=0.91,95% CI 0.69-1.20) and did not improve objective disease response rates in patients. There was no significant difference in grade 3-4 adverse reactions compared to placebo. Conclusion In this meta-analysis of randomised controlled trial studies, we found that chemotherapy in combination with metformin in cancer patients without diabetes did not prolong progression-free survival and overall survival and improved disease control in patients, although there was no significant difference in terms of safety. More high-quality randomised controlled trials are needed in the future to confirm the in vivo anti-tumour activity and survival benefit of metformin.
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Affiliation(s)
- Kang Yang
- Department of Pharmacy, General Hospital of Northern Theater Command of PLA, Shenyang, China
- China Medical University, Shenyang, China
| | - Hao-hao Lu
- Department of Pharmacy, General Hospital of Northern Theater Command of PLA, Shenyang, China
- China Medical University, Shenyang, China
| | - Wei Zhao
- Department of Pharmacy, General Hospital of Northern Theater Command of PLA, Shenyang, China
| | - Qingchun Zhao
- Department of Pharmacy, General Hospital of Northern Theater Command of PLA, Shenyang, China
- China Medical University, Shenyang, China
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14
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Verma S, Chitikela S, Singh V, Khurana S, Pushpam D, Jain D, Kumar S, Gupta Y, Malik PS. A phase II study of metformin plus pemetrexed and carboplatin in patients with non-squamous non-small cell lung cancer (METALUNG). Med Oncol 2023; 40:192. [PMID: 37261532 DOI: 10.1007/s12032-023-02057-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 05/16/2023] [Indexed: 06/02/2023]
Abstract
Immune checkpoint inhibitors (ICIs) ± chemotherapy is the standard treatment for driver mutation-negative non-small cell lung cancer (NSCLC). However, accessibility to ICIs in LMICs is limited due to high cost, and platinum-based chemotherapy remains the mainstay of treatment. Metformin has anticancer properties, and studies suggest synergism between metformin and pemetrexed. Based on preclinical evidence, this combination may be more beneficial for STK11-mutated NSCLC, a subgroup, inherently resistant to ICIs. In this Simon two-stage, single-arm phase 2 trial, we investigated metformin with pemetrexed-carboplatin (PC) in patients with treatment-naive stage IV non-squamous NSCLC. The primary outcome was 6-month progression-free survival (PFS) rate. Secondary outcomes were safety, overall survival (OS), overall response rate (ORR), proportion of STK11 mutation, and effect of STK11 mutation on 6-month PFS rate. The study was terminated for futility after interim analysis. The median follow-up was 34.1 months. The 6-month PFS rate was 28% (95% CI 12.4-0.46). The median PFS and OS were 4.5 (95% CI 2.2-6.1) and 7.4 months (95% CI 5.3-15.3), respectively. The ORR was 72%. Gastrointestinal toxicities were the most common. No grade 4/5 toxicities were reported. Targeted sequencing was possible in nine cases. Two patients had STK11 mutation and a poor outcome (PFS < 12 weeks). We could not demonstrate the benefit of metformin with CP in terms of improvement in 6-month PFS rate; however, the combination was safe (CTRI/2019/02/017815).
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Affiliation(s)
- S Verma
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - S Chitikela
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - V Singh
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - S Khurana
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - D Pushpam
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - D Jain
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - S Kumar
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Y Gupta
- Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, India
| | - P S Malik
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India.
- Department of Medical Oncology, Dr.B.R.A.I.R.C.H., All India Institute of Medical Sciences, Room 245, New Delhi, India.
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15
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Ioakeim-Skoufa I, Tobajas-Ramos N, Menditto E, Aza-Pascual-Salcedo M, Gimeno-Miguel A, Orlando V, González-Rubio F, Fanlo-Villacampa A, Lasala-Aza C, Ostasz E, Vicente-Romero J. Drug Repurposing in Oncology: A Systematic Review of Randomized Controlled Clinical Trials. Cancers (Basel) 2023; 15:cancers15112972. [PMID: 37296934 DOI: 10.3390/cancers15112972] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 05/19/2023] [Accepted: 05/27/2023] [Indexed: 06/12/2023] Open
Abstract
Quality pharmacological treatment can improve survival in many types of cancer. Drug repurposing offers advantages in comparison with traditional drug development procedures, reducing time and risk. This systematic review identified the most recent randomized controlled clinical trials that focus on drug repurposing in oncology. We found that only a few clinical trials were placebo-controlled or standard-of-care-alone-controlled. Metformin has been studied for potential use in various types of cancer, including prostate, lung, and pancreatic cancer. Other studies assessed the possible use of the antiparasitic agent mebendazole in colorectal cancer and of propranolol in multiple myeloma or, when combined with etodolac, in breast cancer. We were able to identify trials that study the potential use of known antineoplastics in other non-oncological conditions, such as imatinib for severe coronavirus disease in 2019 or a study protocol aiming to assess the possible repurposing of leuprolide for Alzheimer's disease. Major limitations of these clinical trials were the small sample size, the high clinical heterogeneity of the participants regarding the stage of the neoplastic disease, and the lack of accounting for multimorbidity and other baseline clinical characteristics. Drug repurposing possibilities in oncology must be carefully examined with well-designed trials, considering factors that could influence prognosis.
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Affiliation(s)
- Ignatios Ioakeim-Skoufa
- WHO Collaborating Centre for Drug Statistics Methodology, Department of Drug Statistics, Division of Health Data and Digitalisation, Norwegian Institute of Public Health, NO-0213 Oslo, Norway
- EpiChron Research Group, Aragon Health Research Institute (IIS Aragón), Miguel Servet University Hospital, ES-50009 Zaragoza, Spain
- Research Network on Chronicity, Primary Care, and Health Promotion (RICAPPS), Institute of Health Carlos III (ISCIII), ES-28029 Madrid, Spain
- Drug Utilization Work Group, Spanish Society of Family and Community Medicine (semFYC), ES-08009 Barcelona, Spain
- Department of Pharmacology, Physiology, and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, ES-50009 Zaragoza, Spain
| | - Natalia Tobajas-Ramos
- Department of Pharmacology, Physiology, and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, ES-50009 Zaragoza, Spain
| | - Enrica Menditto
- Centro Interdipartimentale di Ricerca in Farmacoeconomia e Farmacoutilizzazione (CIRFF), Center of Drug Utilization and Pharmacoeconomics, Department of Pharmacy, University of Naples Federico II, IT-80131 Naples, Italy
| | - Mercedes Aza-Pascual-Salcedo
- EpiChron Research Group, Aragon Health Research Institute (IIS Aragón), Miguel Servet University Hospital, ES-50009 Zaragoza, Spain
- Research Network on Chronicity, Primary Care, and Health Promotion (RICAPPS), Institute of Health Carlos III (ISCIII), ES-28029 Madrid, Spain
- Primary Care Pharmacy Service Zaragoza III, Aragon Health Service (SALUD), ES-50017 Zaragoza, Spain
| | - Antonio Gimeno-Miguel
- EpiChron Research Group, Aragon Health Research Institute (IIS Aragón), Miguel Servet University Hospital, ES-50009 Zaragoza, Spain
- Research Network on Chronicity, Primary Care, and Health Promotion (RICAPPS), Institute of Health Carlos III (ISCIII), ES-28029 Madrid, Spain
| | - Valentina Orlando
- Centro Interdipartimentale di Ricerca in Farmacoeconomia e Farmacoutilizzazione (CIRFF), Center of Drug Utilization and Pharmacoeconomics, Department of Pharmacy, University of Naples Federico II, IT-80131 Naples, Italy
| | - Francisca González-Rubio
- EpiChron Research Group, Aragon Health Research Institute (IIS Aragón), Miguel Servet University Hospital, ES-50009 Zaragoza, Spain
- Drug Utilization Work Group, Spanish Society of Family and Community Medicine (semFYC), ES-08009 Barcelona, Spain
| | - Ana Fanlo-Villacampa
- Department of Pharmacology, Physiology, and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, ES-50009 Zaragoza, Spain
| | - Carmen Lasala-Aza
- Pharmacy Service, Virgen de la Victoria University Hospital, ES-29010 Malaga, Spain
| | - Ewelina Ostasz
- Rehabilitation Centre Vikersund Bad AS, NO-3370 Vikersund, Norway
| | - Jorge Vicente-Romero
- Department of Pharmacology, Physiology, and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, ES-50009 Zaragoza, Spain
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16
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Duan X, Liao B, Liu X, Chen R. Efficacy of metformin adjunctive therapy as the treatment for non-diabetic patients with advanced non-small cell lung cancer: A Systematic review and Meta-analysis. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2023; 28:45. [PMID: 37405073 PMCID: PMC10315409 DOI: 10.4103/jrms.jrms_792_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 03/06/2023] [Accepted: 03/19/2023] [Indexed: 07/06/2023]
Abstract
Background Currently, the anticancer effects of metformin on different types of lung cancer have been frequently studied. However, the relationship between metformin and prognosis in nondiabetic patients with lung cancer remains controversial. To systematically evaluate the efficacy of metformin adjunctive therapy as the treatment for nondiabetic patients with advanced non-small cell lung cancer (NSCLC) to provide an evidence-based reference for clinical medication. Materials and Methods The literatures related to Phase II or III randomized controlled trials (RCTs) of metformin adjunctive therapy in nondiabetic patients with advanced NSCLC, including EMBASE, PubMed, the Cochrane Library, and Scopus database, were retrieved by computer, and the search time ranged from January 2017 to August 2022. The risk of bias assessment tool recommended by Cochrane Systematic Evaluator Manual 5.1.0 was used to evaluate the quality of the RCTs included. Rev Man 5.3 software and STATA15.0 were used for meta-analysis. Results A total of 8 studies were included (925 patients). Meta-analysis results showed that there were no significant differences in progression-free survival (PFS) (hazard ratio [HR] = 0.95, 95% confidence interval [CI]: 0.66-1.36, P = 0.77), overall survival (OS) (HR = 0.89, 95% CI: 0.61-1.30, P = 0.55, n =7), objective response rate (ORR) (odds ratio [OR] = 1.37, 95% CI: 0.76-2.46, P = 0.30), and 1-year PFS rate (OR = 0.87, 95% CI: 0.39-1.94, P = 0.73, n = 3). Sensitivity analysis showed that PFS and OS indexes were stable. Conclusion Metformin adjunctive therapy can improve the DCR of nondiabetic patients with advanced NSCLC. In addition, the patients cannot obtain a prolonged PFS, OS, 1-year PFS rate, and higher ORR rate.
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Affiliation(s)
- Xueyu Duan
- College of Pharmacy, Dali University, Dali, China
- Department of Pharmacy, The Third People's Hospital of Yunnan, Kunming, Yunnan Province, China
| | - Binbin Liao
- College of Pharmacy, Dali University, Dali, China
| | - Xiaobo Liu
- College of Pharmacy, Dali University, Dali, China
| | - Ruixiang Chen
- Department of Pharmacy, The Third People's Hospital of Yunnan, Kunming, Yunnan Province, China
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17
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Lord SR, Harris AL. Is it still worth pursuing the repurposing of metformin as a cancer therapeutic? Br J Cancer 2023; 128:958-966. [PMID: 36823364 PMCID: PMC10006178 DOI: 10.1038/s41416-023-02204-2] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 01/31/2023] [Accepted: 02/06/2023] [Indexed: 02/25/2023] Open
Abstract
Over the past 15 years, there has been great interest in the potential to repurpose the diabetes drug, metformin, as a cancer treatment. However, despite considerable efforts being made to investigate its efficacy in a number of large randomised clinical trials in different tumour types, results have been disappointing to date. This perspective article summarises how interest initially developed in the oncological potential of metformin and the diverse clinical programme of work to date including our contribution to establishing the intra-tumoral pharmacodynamic effects of metformin in the clinic. We also discuss the lessons that can be learnt from this experience and whether a further clinical investigation of metformin in cancer is warranted.
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Affiliation(s)
- Simon R Lord
- Department of Oncology, University of Oxford, Oxford, UK.
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18
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Khan J, Pernicova I, Nisar K, Korbonits M. Mechanisms of ageing: growth hormone, dietary restriction, and metformin. Lancet Diabetes Endocrinol 2023; 11:261-281. [PMID: 36848915 DOI: 10.1016/s2213-8587(23)00001-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 03/01/2023]
Abstract
Tackling the mechanisms underlying ageing is desirable to help to extend the duration and improve the quality of life. Life extension has been achieved in animal models by suppressing the growth hormone-insulin-like growth factor 1 (IGF-1) axis and also via dietary restriction. Metformin has become the focus of increased interest as a possible anti-ageing drug. There is some overlap in the postulated mechanisms of how these three approaches could produce anti-ageing effects, with convergence on common downstream pathways. In this Review, we draw on evidence from both animal models and human studies to assess the effects of suppression of the growth hormone-IGF-1 axis, dietary restriction, and metformin on ageing.
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Affiliation(s)
- Jansher Khan
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Ida Pernicova
- Endocrinology and Metabolic Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Kiran Nisar
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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19
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A Novel Combination of Sotorasib and Metformin Enhances Cytotoxicity and Apoptosis in KRAS-Mutated Non-Small Cell Lung Cancer Cell Lines through MAPK and P70S6K Inhibition. Int J Mol Sci 2023; 24:ijms24054331. [PMID: 36901764 PMCID: PMC10001819 DOI: 10.3390/ijms24054331] [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: 12/30/2022] [Revised: 01/28/2023] [Accepted: 02/10/2023] [Indexed: 02/24/2023] Open
Abstract
Novel inhibitors of KRAS with G12C mutation (sotorasib) have demonstrated short-lasting responses due to resistance mediated by the AKT-mTOR-P70S6K pathway. In this context, metformin is a promising candidate to break this resistance by inhibiting mTOR and P70S6K. Therefore, this project aimed to explore the effects of the combination of sotorasib and metformin on cytotoxicity, apoptosis, and the activity of the MAPK and mTOR pathways. We created dose-effect curves to determine the IC50 concentration of sotorasib, and IC10 of metformin in three lung cancer cell lines; A549 (KRAS G12S), H522 (wild-type KRAS), and H23 (KRAS G12C). Cellular cytotoxicity was evaluated by an MTT assay, apoptosis induction through flow cytometry, and MAPK and mTOR pathways were assessed by Western blot. Our results showed a sensitizing effect of metformin on sotorasib effect in cells with KRAS mutations and a slight sensitizing effect in cells without K-RAS mutations. Furthermore, we observed a synergic effect on cytotoxicity and apoptosis induction, as well as a notable inhibition of the MAPK and AKT-mTOR pathways after treatment with the combination, predominantly in KRAS-mutated cells (H23 and A549). The combination of metformin with sotorasib synergistically enhanced cytotoxicity and apoptosis induction in lung cancer cells, regardless of KRAS mutational status.
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20
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Kurelac I, Cavina B, Sollazzo M, Miglietta S, Fornasa A, De Luise M, Iorio M, Lama E, Traversa D, Nasiri HR, Ghelli A, Musiani F, Porcelli AM, Iommarini L, Gasparre G. NDUFS3 knockout cancer cells and molecular docking reveal specificity and mode of action of anti-cancer respiratory complex I inhibitors. Open Biol 2022; 12:220198. [PMID: 36349549 PMCID: PMC9653258 DOI: 10.1098/rsob.220198] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Inhibition of respiratory complex I (CI) is becoming a promising anti-cancer strategy, encouraging the design and the use of inhibitors, whose mechanism of action, efficacy and specificity remain elusive. As CI is a central player of cellular bioenergetics, a finely tuned dosing of targeting drugs is required to avoid side effects. We compared the specificity and mode of action of CI inhibitors metformin, BAY 87-2243 and EVP 4593 using cancer cell models devoid of CI. Here we show that both BAY 87-2243 and EVP 4593 were selective, while the antiproliferative effects of metformin were considerably independent from CI inhibition. Molecular docking predictions indicated that the high efficiency of BAY 87-2243 and EVP 4593 may derive from the tight network of bonds in the quinone binding pocket, although in different sites. Most of the amino acids involved in such interactions are conserved across species and only rarely found mutated in human. Our data make a case for caution when referring to metformin as a CI-targeting compound, and highlight the need for dosage optimization and careful evaluation of molecular interactions between inhibitors and the holoenzyme.
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Affiliation(s)
- Ivana Kurelac
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy,Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy
| | - Beatrice Cavina
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Manuela Sollazzo
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy
| | - Stefano Miglietta
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy
| | - Agnese Fornasa
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy
| | - Monica De Luise
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy,Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy
| | - Maria Iorio
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Eleonora Lama
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Daniele Traversa
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy
| | - Hamid Razi Nasiri
- Department of Cellular Microbiology, University Hohenheim, Stuttgart, Germany
| | - Anna Ghelli
- Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy,Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy
| | - Francesco Musiani
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy
| | - Anna Maria Porcelli
- Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy,Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy,Interdepartmental Centre for Industrial Research ‘Scienze della Vita e Tecnologie per la Salute’, University of Bologna, Bologna, Italy
| | - Luisa Iommarini
- Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy,Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy
| | - Giuseppe Gasparre
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy,Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy
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21
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Wen J, Yi Z, Chen Y, Huang J, Mao X, Zhang L, Zeng Y, Cheng Q, Ye W, Liu Z, Liu F, Liu J. Efficacy of metformin therapy in patients with cancer: a meta-analysis of 22 randomised controlled trials. BMC Med 2022; 20:402. [PMID: 36280839 PMCID: PMC9594974 DOI: 10.1186/s12916-022-02599-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 10/10/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND To investigate whether metformin monotherapy or adjunctive therapy improves the prognosis in patients with any type of cancer compared to non-metformin users (age ≥18). METHODS Databases (Medline, Embase, and the Cochrane Central Register of Controlled Trials) and clinical trial registries ( ClinicalTrials.gov ; the World Health Organization International Clinical Trials Registry Platform) were screened for randomized, controlled trials (RCT) reporting at least progression-free survival (PFS) and/or overall survival (OS). Main outcome measures included hazard ratios (HR), and combined HRs and 95% confidence intervals (CI) were calculated using random-effects models. RESULTS Of the 8419 records screened, 22 RCTs comprising 5943 participants were included. Pooled HRs were not statistically significant in both PFS (HR 0.97, 95% CI 0.82-1.15, I2 = 50%) and OS (HR 0.98, 95% CI 0.86-1.13, I2 = 33%) for patients with cancer between the metformin and control groups. Subgroup analyses demonstrated that metformin treatment was associated with a marginally significant improvement in PFS in reproductive system cancers (HR 0.86, 95% CI 0.74-1.00) and a significantly worse PFS in digestive system cancers (HR 1.45, 95% CI 1.03-2.04). The PFS or OS was observed consistently across maintenance dose, diabetes exclusion, median follow-up, risk of bias, and combined antitumoral therapies. CONCLUSION Metformin treatment was not associated with cancer-related mortality in adults compared with placebo or no treatment. However, metformin implied beneficial effects in the PFS of the patients with reproductive system cancers but was related to a worse PFS in digestive system cancers. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number CRD42022324672.
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Affiliation(s)
- Jie Wen
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhenjie Yi
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuyao Chen
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Jing Huang
- National Clinical Research Center for Mental Disorders and Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xueyi Mao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Liyang Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yu Zeng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wenrui Ye
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhixiong Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fangkun Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Jingfang Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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22
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Sakamoto K, Okabayashi K, Matsui S, Seishima R, Shigeta K, Kitagawa Y. Association of Tumor Pathological Response with the Use of Metformin During Neoadjuvant Chemoradiotherapy in Rectal and Esophageal/Gastroesophageal Cancer Patients: a Systematic Review and Meta-analysis. J Gastrointest Surg 2022; 26:2227-2236. [PMID: 35829868 DOI: 10.1007/s11605-022-05354-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/30/2022] [Indexed: 01/31/2023]
Abstract
PURPOSE Metformin has been reported to be associated with improved cancer prognosis when used in combination with chemotherapy and/or radiotherapy. In this study, we present a systematic review and meta-analyses of studies evaluating the association of tumor pathological response with the use of metformin during neoadjuvant chemoradiotherapy (NACRT) in rectal and esophageal/gastroesophageal cancer patients. METHODS We systematically searched databases for articles that compared concurrent metformin use with no metformin use in cancer patients treated with NACRT following the PRISMA 2020. The design and quality of the collected studies were reviewed, and meta-analyses were performed on the pathologic complete response (pCR) rate, tumor regression grade (TRG), T factor downstaging, and N factor downstaging. RESULTS Three databases were searched, and 220 papers were screened. Five retrospective cohort study papers were eligible for the meta-analysis, with a total of 2041 patients. The included papers contained only rectal and esophageal/gastroesophageal cancers. In the metformin group, the pCR rate was 26% [20-32%], and metformin was associated with the pCR rate (odds ratio [OR] = 0.51 [0.34-0.76], p < 0.01). Meta-regression analysis of the pCR rate showed a positive correlation with adenocarcinoma (coefficient = 0.13 [0.02-0.25], p = 0.03) and fluoropyrimidine anticancer drug use (coefficient = 0.01 [0.001-0.02], p = 0.03). CONCLUSIONS The results suggest that metformin is associated with pCR rate when used in combination with NACRT. The association of metformin and pCR rate in combination with fluoropyrimidine anticancer drugs was observed mostly for adenocarcinoma patients.
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Affiliation(s)
- Kyoko Sakamoto
- Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 1608582, Japan
| | - Koji Okabayashi
- Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 1608582, Japan
| | - Shimpei Matsui
- Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 1608582, Japan
| | - Ryo Seishima
- Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 1608582, Japan
| | - Kohei Shigeta
- Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 1608582, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 1608582, Japan
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23
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Ohno M, Kitanaka C, Miyakita Y, Tanaka S, Sonoda Y, Mishima K, Ishikawa E, Takahashi M, Yanagisawa S, Ohashi K, Nagane M, Narita Y. Metformin with Temozolomide for Newly Diagnosed Glioblastoma: Results of Phase I Study and a Brief Review of Relevant Studies. Cancers (Basel) 2022; 14:cancers14174222. [PMID: 36077758 PMCID: PMC9454846 DOI: 10.3390/cancers14174222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 11/16/2022] Open
Abstract
Glioblastoma (GBM) inevitably recurs due to a resistance to current standard therapy. We showed that the antidiabetic drug metformin (MF) can induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. In this study, we design a phase I/II study to examine the clinical effect of MF. We aim to determine a recommended phase II MF dose with maintenance temozolomide (TMZ) in patients with newly diagnosed GBM who completed standard concomitant radiotherapy and TMZ. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first six weeks after MF initiation. Three patients were treated with 1500 mg/day MF and four patients were treated with 2250 mg/day MF between February 2021 and January 2022. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, all of which were manageable. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up session. The MF dose of up to 2250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to a phase II study with 2250 mg/day MF.
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Affiliation(s)
- Makoto Ohno
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Chifumi Kitanaka
- Department of Molecular Cancer Science, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan
| | - Yasuji Miyakita
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Shota Tanaka
- Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Yukihiko Sonoda
- Department of Neurosurgery, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan
| | - Kazuhiko Mishima
- Department of Neuro-Oncology/Neurosurgery, International Medical Center, Saitama Medical University, Hidaka 350-1298, Japan
| | - Eiichi Ishikawa
- Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba 350-8576, Japan
| | - Masamichi Takahashi
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Shunsuke Yanagisawa
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Ken Ohashi
- Department of General Internal Medicine, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Motoo Nagane
- Department of Neurosurgery, Kyorin University Faculty of Medicine, Mitaka 181-8611, Japan
| | - Yoshitaka Narita
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
- Correspondence: ; Tel.: +81-3-3542-2511
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24
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Metformin modulate immune fitness in hepatocellular carcinoma: Molecular and cellular approach. Int Immunopharmacol 2022; 109:108889. [DOI: 10.1016/j.intimp.2022.108889] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 12/16/2022]
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25
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Will We Unlock the Benefit of Metformin for Patients with Lung Cancer? Lessons from Current Evidence and New Hypotheses. Pharmaceuticals (Basel) 2022; 15:ph15070786. [PMID: 35890085 PMCID: PMC9318003 DOI: 10.3390/ph15070786] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 11/16/2022] Open
Abstract
Metformin has been under basic and clinical study as an oncological repurposing pharmacological agent for several years, stemming from observational studies which consistently evidenced that subjects who were treated with metformin had a reduced risk for development of cancer throughout their lives, as well as improved survival outcomes when diagnosed with neoplastic diseases. As a result, several basic science studies have attempted to dissect the relationship between metformin’s metabolic mechanism of action and antineoplastic cellular signaling pathways. Evidence in this regard was compelling enough that a myriad of randomized clinical trials was planned and conducted in order to establish the effect of metformin treatment for patients with diverse neoplasms, including lung cancer. As with most novel antineoplastic agents, early results from these studies have been mostly discouraging, though a recent analysis that incorporated body mass index may provide significant information regarding which patient subgroups might derive the most benefit from the addition of metformin to their anticancer treatment. Much in line with the current pipeline for anticancer agents, it appears that the benefit of metformin may be circumscribed to a specific patient subgroup. If so, addition of metformin to antineoplastic agents could prove one of the most cost-effective interventions proposed in the context of precision oncology. Currently published reviews mostly rely on a widely questioned mechanism of action by metformin, which fails to consider the differential effects of the drug in lean vs. obese subjects. In this review, we analyze the pre-clinical and clinical information available to date regarding the use of metformin in various subtypes of lung cancer and, further, we present evidence as to the differential metabolic effects of metformin in lean and obese subjects where, paradoxically, the obese subjects have reported more benefit with the addition of metformin treatment. The novel mechanisms of action described for this biguanide may explain the different results observed in clinical trials published in the last decade. Lastly, we present novel hypothesis regarding potential biomarkers to identify who might reap benefit from this intervention, including the role of prolyl hydroxylase domain 3 (PHD3) expression to modify metabolic phenotypes in malignant diseases.
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26
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van Hattum JW, de Ruiter BM, Oddens JR, de Reijke TM, Wilmink JW, Molenaar RJ. The Effect of Metformin on Bladder Cancer Incidence and Outcomes: A Systematic Review and Meta-Analysis. Bladder Cancer 2022; 8:211-228. [PMID: 38993366 PMCID: PMC11181685 DOI: 10.3233/blc-211653] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/17/2022] [Indexed: 12/20/2022]
Abstract
BACKGROUND Effective oral treatment options for urothelial bladder cancer (BC) are lacking. Metformin, the most frequently used oral drug in type II diabetes mellitus, has putative anticancer properties and could, therefore, influence BC incidence and treatment outcomes. We systematically reviewed the current literature regarding the effect of metformin on BC incidence and oncological outcomes in non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). METHODS This review was conducted according to the PRISMA guidelines. Literature was gathered through a systematic search in PubMed/Medline, EMBASE and the Cochrane library. Risk of bias was determined using the Cochrane risk-of-bias tool for randomized trials and the Newcastle-Ottawa Scale for non-randomized trials. Hazard ratios (HRs) were extracted and pooled in a random-effects meta-analysis. RESULTS We reviewed 13 studies, including 3,315,320 patients, considering the risk of developing BC after metformin exposure and 9 studies, including 4,006 patients, on oncological outcomes of patients with BC. Metformin did not affect BC incidence (HR 0.97, 95% CI 0.87 -1.09) or oncological outcomes for NMIBC but did show a reduced risk of recurrence (HR 0.52, 95% CI 0.32 -0.84), cancer-specific mortality (HR 0.58, 95% CI 0.43 -0.78) and overall mortality (HR 0.66, 95% CI 0.47 -0.92) in MIBC. CONCLUSIONS The role of metformin in the prevention and treatment of BC in patients remains unclear. Although a beneficial effect of metformin on treatment outcomes of certain stages of BC may exist, a definitive conclusion cannot be drawn. Prospective clinical trials are needed to assess the efficacy of metformin for BC treatment.
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Affiliation(s)
- Jons W. van Hattum
- Department of Urology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Ben Max de Ruiter
- Department of Urology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Jorg R. Oddens
- Department of Urology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Theo M. de Reijke
- Department of Urology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Johanna W. Wilmink
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Remco J. Molenaar
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
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27
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Metformin and Cancer, an Ambiguanidous Relationship. Pharmaceuticals (Basel) 2022; 15:ph15050626. [PMID: 35631452 PMCID: PMC9144507 DOI: 10.3390/ph15050626] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/10/2022] [Accepted: 05/12/2022] [Indexed: 01/27/2023] Open
Abstract
The deregulation of energetic and cellular metabolism is a signature of cancer cells. Thus, drugs targeting cancer cell metabolism may have promising therapeutic potential. Previous reports demonstrate that the widely used normoglycemic agent, metformin, can decrease the risk of cancer in type 2 diabetics and inhibit cell growth in various cancers, including pancreatic, colon, prostate, ovarian, and breast cancer. While metformin is a known adenosine monophosphate-activated protein kinase (AMPK) agonist and an inhibitor of the electron transport chain complex I, its mechanism of action in cancer cells as well as its effect on cancer metabolism is not clearly established. In this review, we will give an update on the role of metformin as an antitumoral agent and detail relevant evidence on the potential use and mechanisms of action of metformin in cancer. Analyzing antitumoral, signaling, and metabolic impacts of metformin on cancer cells may provide promising new therapeutic strategies in oncology.
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28
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Shen W, He J, Hou T, Si J, Chen S. Common Pathogenetic Mechanisms Underlying Aging and Tumor and Means of Interventions. Aging Dis 2022; 13:1063-1091. [PMID: 35855334 PMCID: PMC9286910 DOI: 10.14336/ad.2021.1208] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 12/07/2021] [Indexed: 11/22/2022] Open
Abstract
Recently, there has been an increase in the incidence of malignant tumors among the older population. Moreover, there is an association between aging and cancer. During the process of senescence, the human body suffers from a series of imbalances, which have been shown to further accelerate aging, trigger tumorigenesis, and facilitate cancer progression. Therefore, exploring the junctions of aging and cancer and searching for novel methods to restore the junctions is of great importance to intervene against aging-related cancers. In this review, we have identified the underlying pathogenetic mechanisms of aging-related cancers by comparing alterations in the human body caused by aging and the factors that trigger cancers. We found that the common mechanisms of aging and cancer include cellular senescence, alterations in proteostasis, microbiota disorders (decreased probiotics and increased pernicious bacteria), persistent chronic inflammation, extensive immunosenescence, inordinate energy metabolism, altered material metabolism, endocrine disorders, altered genetic expression, and epigenetic modification. Furthermore, we have proposed that aging and cancer have common means of intervention, including novel uses of common medicine (metformin, resveratrol, and rapamycin), dietary restriction, and artificial microbiota intervention or selectively replenishing scarce metabolites. In addition, we have summarized the research progress of each intervention and revealed their bidirectional effects on cancer progression to compare their reliability and feasibility. Therefore, the study findings provide vital information for advanced research studies on age-related cancers. However, there is a need for further optimization of the described methods and more suitable methods for complicated clinical practices. In conclusion, targeting aging may have potential therapeutic effects on aging-related cancers.
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Affiliation(s)
- Weiyi Shen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China.
- Institute of Gastroenterology, Zhejiang University, Hangzhou 310016, Zhejiang, China.
- Prevention and Treatment Research Center for Senescent Disease, Zhejiang University School of Medicine, Zhejiang, China
| | - Jiamin He
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China.
- Institute of Gastroenterology, Zhejiang University, Hangzhou 310016, Zhejiang, China.
- Prevention and Treatment Research Center for Senescent Disease, Zhejiang University School of Medicine, Zhejiang, China
| | - Tongyao Hou
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China.
- Institute of Gastroenterology, Zhejiang University, Hangzhou 310016, Zhejiang, China.
- Prevention and Treatment Research Center for Senescent Disease, Zhejiang University School of Medicine, Zhejiang, China
- Correspondence should be addressed to: Dr. Shujie Chen (), Dr. Jianmin Si () and Dr. Tongyao Hou (), Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang, China
| | - Jianmin Si
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China.
- Institute of Gastroenterology, Zhejiang University, Hangzhou 310016, Zhejiang, China.
- Prevention and Treatment Research Center for Senescent Disease, Zhejiang University School of Medicine, Zhejiang, China
- Correspondence should be addressed to: Dr. Shujie Chen (), Dr. Jianmin Si () and Dr. Tongyao Hou (), Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang, China
| | - Shujie Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China.
- Institute of Gastroenterology, Zhejiang University, Hangzhou 310016, Zhejiang, China.
- Prevention and Treatment Research Center for Senescent Disease, Zhejiang University School of Medicine, Zhejiang, China
- Correspondence should be addressed to: Dr. Shujie Chen (), Dr. Jianmin Si () and Dr. Tongyao Hou (), Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang, China
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29
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Chen L, Yin Y, Liu G. Metformin alleviates bevacizumab-induced vascular endothelial injury by up-regulating GDF15 and activating the PI3K/AKT/FOXO/PPARγ signaling pathway. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1547. [PMID: 34790753 PMCID: PMC8576656 DOI: 10.21037/atm-21-4764] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/02/2021] [Indexed: 01/04/2023]
Abstract
Background Previous studies have reported that the combination of metformin and bevacizumab exhibit favorable efficacy in the treatment of cancer patients, and metformin possesses effects on relieving vascular injury in multiple diseases. Nonetheless, the effect of metformin in alleviating bevacizumab-induced vascular injury remains unknown. Therefore, the present study aimed to investigate the impact of metformin on apoptosis, vascular endothelial injury marker expressions, and inflammation in human umbilical vein endothelial cells (HUVECs), as well as its possible molecular mechanism. Methods HUVECs were treated with bevacizumab, metformin or both, and subsequently treated with growth differentiation factor 15 (GDF15) overexpression plasmid, negative control (NC) plasmid, GDF15 small interfering ribonucleic acid (siRNA), NC siRNA, and the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, respectively. After treatment, apoptosis, levels of endothelial injury biomarkers and the potential downstream proteins were detected. Results Bevacizumab increased the levels of apoptosis, vascular endothelial injury marker expressions and pro-inflammatory cytokine expressions in HUVECs, while metformin alleviated these effects in bevacizumab-treated HUVECs. Furthermore, GDF15 overexpression reduced the apoptosis, vascular endothelial injury marker expressions, pro-inflammatory cytokine expressions, and activated the PI3K/protein kinase B (AKT)/forkhead box O (FOXO)/peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway in bevacizumab-treated HUVECs. Subsequently, GDF15 siRNA reduced the effects of metformin on the bevacizumab-induced vascular endothelial injury (as described above) in HUEVCs. Lastly, the PI3K inhibitor exhibited similar effects to those of GDF15 siRNA in bevacizumab-treated HUVECs. Conclusions Metformin protected against bevacizumab-induced vascular endothelial injury via activation of GDF15 and the PI3K/AKT/FOXO/PPARγ signaling pathway.
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Affiliation(s)
- Liqiang Chen
- Cardiovascular Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yajuan Yin
- Cardiovascular Department, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Gang Liu
- Cardiovascular Department, The First Hospital of Hebei Medical University, Shijiazhuang, China
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Tully E, Bharti S, Woo J, Bhujwalla Z, Gabrielson E. Biguanide drugs enhance cytotoxic effects of cisplatin by depleting aspartate and NAD+ in sensitive cancer cells. Cancer Biol Ther 2021; 22:579-586. [PMID: 34720054 DOI: 10.1080/15384047.2021.1982599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Biguanide drugs (metformin and phenformin) have drawn interest for potential cancer treatments, and laboratory studies show that some cancer cells are selectively sensitive to growth-inhibitory effects of biguanides. Examining metabolic pathways affected by biguanide treatments in cancer cells that are highly sensitive to biguanides, we found that biguanide treatment depletes cellular levels of both aspartate and NAD+. Experiments to replenish these metabolites or block steps of the aspartate-malate shuttle suggest that depletion of both metabolites, rather than either aspartate of NAD+ individually, is critical for growth-inhibitory effects of biguanide exposure. Even in sensitive cancer cells, though, biguanide treatment alone over a broad range of doses only inhibits cell replication without significantly affecting cell viability. Noting that clinical observations of biguanide efficacy have used combinations of agents that typically include cisplatin, we found that biguanide treatment at a cytostatic level substantially decreases survival of lung cancer and breast cancer cells when co-treated with cisplatin at doses that alone are also non-cytotoxic. This striking enhancement of cisplatin toxicity by biguanides depends on reductions of levels of NAD+ and aspartate, since addition of either of these metabolites prevented this potentiation of cisplatin cytotoxicity. Thus, biguanide drugs can have cytotoxic effects when used in combination with other cancer drugs, such as cisplatin, and depleting cellular levels of NAD+ and aspartate is critical for enhancing the cytotoxicity of cisplatin by biguanide drugs in sensitive cancer cells.
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Affiliation(s)
- Ellen Tully
- The Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Santosh Bharti
- The Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Juhyung Woo
- The Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Zaver Bhujwalla
- The Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.,The Department of Oncology and the Sydney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Edward Gabrielson
- The Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.,The Department of Oncology and the Sydney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Brancher S, Ribeiro AE, Toporcov TN, Weiderpass E. The role of metformin on lung cancer survival: the first systematic review and meta-analysis of observational studies and randomized clinical trials. J Cancer Res Clin Oncol 2021; 147:2819-2836. [PMID: 34264392 DOI: 10.1007/s00432-021-03728-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 07/04/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE To assess the effects of metformin use on lung cancer (LC) survival according to summarized results from observational studies (OBs) and randomized clinical trials (RCTs). METHODS We systematically searched electronic databases and, to our knowledge, for the first time, RCTs were included in a systematic review and meta-analysis about the role of metformin on LC survival. We carried out meta-analyses separately for OBs and RCTs. Analyses for overall survival (OS) concerning OBs were stratified by studies with and without time-dependent approach. Subgroup analyses were adopted for OBs to identify the sources of heterogeneity. Included studies were assessed for quality. RESULTS We identified ten OBs and four RCTs. For OBs, metformin use was associated with improved OS for LC patients. Only two studies used time-dependent approach in which a higher ratio was found when compared to the non-use of the time-dependent analysis in eight studies. OBs were classified as high quality but the risk of bias was "unclear" in eight OBs due to absence of the time-dependent analysis. For RCTs, metformin use was not beneficial for OS and neither for progression-free survival. Heterogeneous quality was found among RCTs. Sources of bias that could alter significantly the results or raise doubts were identified in RCTs. CONCLUSION Time-dependent analysis should be considered an appropriate strategy for OBs focused on the metformin use for LC patients' survival, and further studies applying this approach are required. More well-designed RCTs are needed to provide consistent results for the association between metformin use and LC survival.
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Affiliation(s)
- Suzan Brancher
- Department of Epidemiology, School of Public Health, University of São Paulo, Av. Dr. Arnaldo 715, Cerqueira César, São Paulo, SP, CEP 01246-904, Brazil.
| | - Ana Elisa Ribeiro
- Department of Dentistry, State University of Ponta Grossa, Ponta Grossa, Brazil
| | - Tatiana Natasha Toporcov
- Department of Epidemiology, School of Public Health, University of São Paulo, Av. Dr. Arnaldo 715, Cerqueira César, São Paulo, SP, CEP 01246-904, Brazil
| | - Elisabete Weiderpass
- International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France
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Wang JL, Tsai YT, Lin CH, Cidem A, Staniczek T, Chang GRL, Yen CC, Chen W, Chong KY, Chen CM. Benefits of Metformin Combined with Pemetrexed-Based Platinum Doublets as a First-Line Therapy for Advanced Lung Adenocarcinoma Patients with Diabetes. Biomolecules 2021; 11:biom11081252. [PMID: 34439918 PMCID: PMC8392201 DOI: 10.3390/biom11081252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 08/06/2021] [Accepted: 08/19/2021] [Indexed: 01/20/2023] Open
Abstract
Lung cancer remains a challenge in daily practice. Chemotherapy is first considered for advanced lung adenocarcinoma bearing no active driver mutations. Maintaining drug efficacy and overcoming drug resistance are essential. This study aimed to explore the real-world use of anti-diabetic agent metformin in combination with pemetrexed-based platinum doublets in a first-line setting. We retrospectively collected data during 2004~2013 from TaiwaN's National Health Insurance Research Database to access the survival benefit of metformin combined with pemetrexed-based platinum doublets as a first-line therapy for diabetic patients with advanced lung adenocarcinoma. Demographic data and information regarding platinum reagents, diabetes medications, and metformin doses were gathered, and overall survival status regarding metformin use was analyzed. Overall survival status based on the daily dose and the calculated cumulative defined daily dose (DDD) of metformin prescribed during the first 3 months after lung cancer was diagnosed was also assessed. A total of 495 patients were enrolled with a mean age of 67 years old, and the majority of the patients were male. After adjusting for age, sex, diabetes medication, and platinum reagents used, the adjusted hazard ratio (HR) for the metformin-user group was 0.61 (95% confidence interval (CI); 0.46~0.79; p < 0.001). The metformin-user group had a survival benefit (log-rank p < 0.001). We analyzed metformin dosing during the first 3 months after lung cancer diagnosis, and for a daily dose ≥ 1500 mg, the adjusted hazard ratio (aHR) was 0.42 (95% CI; 0.27~0.65; p < 0.001). Regarding the cumulative DDD of metformin, a DDD equal to or exceeding 21 resulted in aHR of 0.48 (95% CI; 0.34~0.69; p < 0.001). In this study, we found that the combination of metformin and pemetrexed-based platinum doublets provides a robust survival benefit as a first-line therapy for diabetic patients with advanced lung adenocarcinoma. It is worth conducting a large and randomized clinical trial to further investigate the antitumor effects of metformin on advanced lung adenocarcinoma when used as a first-ling therapy, including in non-diabetic patients.
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Affiliation(s)
- Jiun-Long Wang
- Department of Life Sciences, and Ph.D. Program in Translational Medicine, College of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan; (J.-L.W.); (A.C.); (T.S.); (G.R.-L.C.)
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan
| | - Yi-Ting Tsai
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan;
| | - Ching-Heng Lin
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan;
- Department of Health Care Management, National Taipei University of Nursing and Health Sciences, Taipei 112, Taiwan
- Department of Public Health, Fu Jen Catholic University, Taipei 242, Taiwan
| | - Abdulkadir Cidem
- Department of Life Sciences, and Ph.D. Program in Translational Medicine, College of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan; (J.-L.W.); (A.C.); (T.S.); (G.R.-L.C.)
| | - Theresa Staniczek
- Department of Life Sciences, and Ph.D. Program in Translational Medicine, College of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan; (J.-L.W.); (A.C.); (T.S.); (G.R.-L.C.)
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, and Center of Excellence in Dermatology, Heidelberg University, 69117 Mannheim, Germany
| | - Gary Ro-Lin Chang
- Department of Life Sciences, and Ph.D. Program in Translational Medicine, College of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan; (J.-L.W.); (A.C.); (T.S.); (G.R.-L.C.)
| | - Chih-Ching Yen
- Department of Internal Medicine, China Medical University Hospital, and College of Health Care, China Medical University, Taichung 404, Taiwan;
| | - Wei Chen
- Division of Pulmonary and Critical Care Medicine, Chia-Yi Christian Hospital, Chiayi 600, Taiwan;
| | - Kowit-Yu Chong
- Department of Medical Biotechnology and Laboratory Science and Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Hyperbaric Oxygen Medical Research Lab, Bone and Joint Research Center, and Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan
- Correspondence: (K.-Y.C.); (C.-M.C.); Tel.: +886-3-2118393 (K.-Y.C.); +886-4-22856309 (C.-M.C.)
| | - Chuan-Mu Chen
- Department of Life Sciences, and Ph.D. Program in Translational Medicine, College of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan; (J.-L.W.); (A.C.); (T.S.); (G.R.-L.C.)
- The iEGG and Animal Biotechnology Center, and RongHsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Correspondence: (K.-Y.C.); (C.-M.C.); Tel.: +886-3-2118393 (K.-Y.C.); +886-4-22856309 (C.-M.C.)
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Singh SK, Apata T, Singh S, McFadden M, Singh R. Clinical Implication of Metformin in Relation to Diabetes Mellitus and Ovarian Cancer. Biomedicines 2021; 9:biomedicines9081020. [PMID: 34440224 PMCID: PMC8394937 DOI: 10.3390/biomedicines9081020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/11/2021] [Accepted: 08/13/2021] [Indexed: 11/16/2022] Open
Abstract
Since multiple reports established an association between diabetes mellitus and various cancers, emerging studies have surfaced to understand the effects of metformin as an anti-cancer agent. Although there was previous, but conflicting evidence, of a relationship between diabetes and ovarian cancer (OvCa), recent studies have supported this association. The mechanism of cancer development in patients with diabetes is likely to involve hyperglycemia, hyperinsulinemia, chronic inflammation, reactive oxygen species, regulation of cellular homeostasis, and activation of various pathways that lead to tumor cell proliferation. Preclinical evidence indicating that metformin, a medication commonly used to treat type 2 diabetes mellitus, may protect against OvCa. Metformin exerts anti-cancer properties by activating the MAPK pathway, inhibiting the PI3K/AKT/mTOR pathway, increasing tumor suppressor genes, inducing G2/M cycle arrest, and various other processes. Several studies have shown the efficacy of metformin as an adjunct with standard chemotherapeutic agents due to its synergistic effects on OvCa cells. This review highlights the epidemiologic evidence supporting a link between diabetes and OvCa, the fundamental molecular mechanism underlying carcinogenesis in patients with diabetes, the anti-cancer effects of metformin, and the need for further clinical investigations on combination therapies with metformin and standard chemotherapeutic agents for OvCa.
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Affiliation(s)
- Santosh Kumar Singh
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA; (S.K.S.); (T.A.); (M.M.)
| | - Tejumola Apata
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA; (S.K.S.); (T.A.); (M.M.)
| | - Shriti Singh
- Department of Kriya Sharir, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India;
| | - Melayshia McFadden
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA; (S.K.S.); (T.A.); (M.M.)
| | - Rajesh Singh
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA; (S.K.S.); (T.A.); (M.M.)
- Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
- Correspondence: ; Tel.: +1-404-756-6661; Fax: +1-404-752-1179
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Jacobi O, Landman Y, Reinhorn D, Icht O, Sternschuss M, Rotem O, Finkel I, Allen AM, Dudnik E, Goldstein DA, Zer A. The Relationship of Diabetes Mellitus to Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer. Oncology 2021; 99:555-561. [PMID: 34247166 DOI: 10.1159/000516671] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 04/21/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICI) are the new standard therapy in patients with metastatic NSCLC (mNSCLC). Metformin, previously associated with improved chemotherapy efficacy in diabetic and nondiabetic cancer patients, was recently associated with increased ICI efficacy. In this study, we aimed to explore the correlations between diabetes mellitus (DM), metformin use, and benefit from ICI in mNSCLC patients. METHODS All mNSCLC patients treated with ICI in our center between February 2015 and April 2018 were identified. Demographic and clinical data were extracted retrospectively. Cox proportional hazards regression, t tests, and χ2 tests were employed to evaluate associations of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR), with DM status, metformin use, and HbA1c levels, as appropriate. RESULTS Of 249 mNSCLC patients treated with ICI, 57 (22.8%) had DM. Thirty-seven (64.9% of all diabetic patients) patients were treated with metformin. A significant negative correlation of DM with PFS and OS was demonstrated (HR 1.5 [1.01-2.06], p = 0.011, and HR 1.5 [1.08-2.08], p = 0.017, respectively). Metformin exposure had no significant correlation with PFS or OS in diabetic mNSCLC patients (HR 1.08 [0.61-1.93], p = 0.79, and HR 1.29 [0.69-2.39], p = 0.42, respectively). There were no differences between groups with respect to ORR and DCR. CONCLUSION Our data show a potential negative relationship between DM and ICI efficacy in mNSCLC patients. In contrast to reports with chemotherapy, we found no positive relationship between metformin use and ICI therapy in diabetic patients with mNSCLC. Further studies are needed to evaluate the effect of metformin in nondiabetic mNSCLC patients.
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Affiliation(s)
- Oded Jacobi
- Davidoff Cancer Center, Rabin Medical Center, Petach-Tiqwa, Israel
| | - Yosef Landman
- Davidoff Cancer Center, Rabin Medical Center, Petach-Tiqwa, Israel
| | - Daniel Reinhorn
- Davidoff Cancer Center, Rabin Medical Center, Petach-Tiqwa, Israel
| | - Oded Icht
- Davidoff Cancer Center, Rabin Medical Center, Petach-Tiqwa, Israel
| | | | - Ofer Rotem
- Davidoff Cancer Center, Rabin Medical Center, Petach-Tiqwa, Israel
| | - Inbar Finkel
- Davidoff Cancer Center, Rabin Medical Center, Petach-Tiqwa, Israel
| | - Aaron M Allen
- Davidoff Cancer Center, Rabin Medical Center, Petach-Tiqwa, Israel
| | - Elizabeth Dudnik
- Davidoff Cancer Center, Rabin Medical Center, Petach-Tiqwa, Israel
| | | | - Alona Zer
- Davidoff Cancer Center, Rabin Medical Center, Petach-Tiqwa, Israel
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Wang JL, Lan YW, Tsai YT, Chen YC, Staniczek T, Tsou YA, Yen CC, Chen CM. Additive Antiproliferative and Antiangiogenic Effects of Metformin and Pemetrexed in a Non-Small-Cell Lung Cancer Xenograft Model. Front Cell Dev Biol 2021; 9:688062. [PMID: 34235153 PMCID: PMC8255984 DOI: 10.3389/fcell.2021.688062] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 05/31/2021] [Indexed: 12/16/2022] Open
Abstract
Lung cancer is heterogeneous and challenging to cope with once it has progressed. Chemotherapy is the first step once no active driver mutation has been discovered. Non-antitumor drugs have been found to be beneficial when used as adjuvants to chemotherapy. In this study, the additive effect and mechanism of metformin combined with pemetrexed in non-small-cell lung cancer (NSCLC) cells were elucidated. Three NSCLC cell lines, A549, H1975, and HCC827, were used to analyze tumor cell proliferation, colony formation and the cell cycle in vitro when exposed to metformin alone, pemetrexed alone or their combination. We found that combination treatment in three cell lines exerted antiproliferative effects through cell cycle arrest in the S phase. An ex vivo chicken chorioallantoic membrane (CAM) assay was used to examine the antiangiogenic effect of metformin combined with pemetrexed on vascular structure formation. We further created an A549 orthotopic xenograft model with an in vivo imaging system (IVIS) and explored the associated indicators involved in the tumorigenic process. The in vitro results showed that the combination of metformin and pemetrexed exhibited an antiproliferative effect in reducing cell viability and colony formation, the downregulation of cyclin D1 and A2 and the upregulation of CDKN1B, which are involved in the G1/S phase. For antiangiogenic effects, the combination therapy inhibited the vascular structure, as proven by the CAM assay. We elucidated that combination therapy could target VEGFA and Endoglin by RT-qPCR, ELISA and histopathological findings in an A549 orthotopic NSCLC xenograft model. Our research demonstrated the additive antiproliferative and antiangiogenic effects of the combination of metformin with pemetrexed in NSCLC and could be applied to clinical lung cancer therapy.
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Affiliation(s)
- Jiun-Long Wang
- Ph.D. Program in Translational Medicine, Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.,Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ying-Wei Lan
- Ph.D. Program in Translational Medicine, Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Yi-Ting Tsai
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ying-Cheng Chen
- Ph.D. Program in Translational Medicine, Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Theresa Staniczek
- Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Yung-An Tsou
- Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Chih-Ching Yen
- Department of Internal Medicine, China Medical University Hospital, College of Health Care, China Medical University, Taichung, Taiwan
| | - Chuan-Mu Chen
- Ph.D. Program in Translational Medicine, Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.,The iEGG and Animal Biotechnology Center, Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
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Khurshed M, Molenaar RJ, van Linde ME, Mathôt RA, Struys EA, van Wezel T, van Noorden CJF, Klümpen HJ, Bovée JVMG, Wilmink JW. A Phase Ib Clinical Trial of Metformin and Chloroquine in Patients with IDH1-Mutated Solid Tumors. Cancers (Basel) 2021; 13:cancers13102474. [PMID: 34069550 PMCID: PMC8161333 DOI: 10.3390/cancers13102474] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/13/2021] [Accepted: 05/15/2021] [Indexed: 12/23/2022] Open
Abstract
Simple Summary Mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in high-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma. Due to the lack of effective treatment options, these aggressive types of cancer have a dismal outcome. The metabolism of IDH1-mutated cancer cells is reprogrammed in order to produce the oncometabolite D-2-hydroxyglutarate (D-2HG). In this clinical trial, we used the oral antidiabetic drug metformin and the oral antimalarial drug chloroquine to disrupt the vulnerable metabolism of IDH1-mutated solid tumors. We found that the combination regimen of metformin and chloroquine is well tolerated, but the combination did not induce a clinical response in this patient population. Secondly, we confirmed the clinical usefulness of D/L-2HG ratios in serum as a biomarker and the ddPCR-facilitated detection of an IDH1 mutation in circulating DNA from peripheral blood. Abstract Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid IDH1-mutated tumors produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are more vulnerable to disruption of their metabolism. Methods: Patients with IDH1-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine. The primary objective was to determine the occurrence of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Radiological and biochemical tumor responses to metformin and chloroquine were investigated using CT/MRI scans and magnetic resonance spectroscopy (MRS) measurements of D-2HG levels in serum. Results: Seventeen patients received study treatment for a median duration of 43 days (range: 7–74 days). Of twelve evaluable patients, 10 patients discontinued study medication because of progressive disease and two patients due to toxicity. None of the patients experienced a DLT. The MTD was determined to be 1500 mg of metformin two times a day and 200 mg of chloroquine once a day. A serum D/L-2HG ratio of ≥4.5 predicted the presence of an IDH1 mutation with a sensitivity of 90% and a specificity of 100%. By utilization of digital droplet PCR on plasma samples, we were able to detect tumor-specific IDH1 hotspot mutations in circulating tumor DNA (ctDNA) in investigated patients. Conclusion: Treatment of advanced IDH1-mutated solid tumors with metformin and chloroquine was well tolerated but did not induce a clinical response in this phase Ib clinical trial.
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Affiliation(s)
- Mohammed Khurshed
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (M.K.); (R.J.M.); (M.E.v.L.); (H.-J.K.)
- Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Remco J. Molenaar
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (M.K.); (R.J.M.); (M.E.v.L.); (H.-J.K.)
- Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Myra E. van Linde
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (M.K.); (R.J.M.); (M.E.v.L.); (H.-J.K.)
| | - Ron A. Mathôt
- Department of Clinical Pharmacology, Cancer Center Amsterdam, Amsterdam UMC location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Eduard A. Struys
- Department of Clinical Chemistry, Cancer Center Amsterdam, Amsterdam UMC location VU, University Medical Center, 1081 HV Amsterdam, The Netherlands;
| | - Tom van Wezel
- Department of Pathology, Leiden University Medical Center, 2311 EZ Leiden, The Netherlands; (T.v.W.); (J.V.M.G.B.)
| | - Cornelis J. F. van Noorden
- Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia
| | - Heinz-Josef Klümpen
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (M.K.); (R.J.M.); (M.E.v.L.); (H.-J.K.)
| | - Judith V. M. G. Bovée
- Department of Pathology, Leiden University Medical Center, 2311 EZ Leiden, The Netherlands; (T.v.W.); (J.V.M.G.B.)
| | - Johanna W. Wilmink
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (M.K.); (R.J.M.); (M.E.v.L.); (H.-J.K.)
- Correspondence:
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Sebestyén A, Kopper L, Dankó T, Tímár J. Hypoxia Signaling in Cancer: From Basics to Clinical Practice. Pathol Oncol Res 2021; 27:1609802. [PMID: 34257622 PMCID: PMC8262153 DOI: 10.3389/pore.2021.1609802] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 12/24/2022]
Abstract
Cancer hypoxia, recognized as one of the most important hallmarks of cancer, affects gene expression, metabolism and ultimately tumor biology-related processes. Major causes of cancer hypoxia are deficient or inappropriate vascularization and systemic hypoxia of the patient (frequently induced by anemia), leading to a unique form of genetic reprogramming by hypoxia induced transcription factors (HIF). However, constitutive activation of oncogene-driven signaling pathways may also activate hypoxia signaling independently of oxygen supply. The consequences of HIF activation in tumors are the angiogenic phenotype, a novel metabolic profile and the immunosuppressive microenvironment. Cancer hypoxia and the induced adaptation mechanisms are two of the major causes of therapy resistance. Accordingly, it seems inevitable to combine various therapeutic modalities of cancer patients by existing anti-hypoxic agents such as anti-angiogenics, anti-anemia therapies or specific signaling pathway inhibitors. It is evident that there is an unmet need in cancer patients to develop targeted therapies of hypoxia to improve efficacies of various anti-cancer therapeutic modalities. The case has been opened recently due to the approval of the first-in-class HIF2α inhibitor.
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Affiliation(s)
- Anna Sebestyén
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - László Kopper
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Titanilla Dankó
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - József Tímár
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
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Liu S, Polsdofer EV, Zhou L, Ruan S, Lyu H, Hou D, Liu H, Thor AD, He Z, Liu B. Upregulation of endogenous TRAIL-elicited apoptosis is essential for metformin-mediated antitumor activity against TNBC and NSCLC. MOLECULAR THERAPY-ONCOLYTICS 2021; 21:303-314. [PMID: 34141868 PMCID: PMC8167201 DOI: 10.1016/j.omto.2021.04.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 04/24/2021] [Indexed: 12/24/2022]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promising antitumor activity in preclinical studies. However, the efficacy of recombinant TRAIL in clinical trials is compromised by its short serum half-life and low in vivo stability. Induction of endogenous TRAIL may overcome the limitations and become a new strategy for cancer treatment. Here, we discovered that metformin increased TRAIL expression and induced apoptosis in triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) cells. Metformin did not alter the expression of TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). Metformin-upregulated TRAIL was secreted into conditioned medium (CM) and found to be functional, since the CM promoted TNBC cells undergoing apoptosis, which was abrogated by a recombinant TRAIL-R2-Fc chimera. Moreover, blockade of TRAIL binding to DR4/DR5 or specific knockdown of TRAIL expression significantly attenuated metformin-induced apoptosis. Studies with a tumor xenograft model revealed that metformin not only significantly inhibited tumor growth but also elicited apoptosis and enhanced TRAIL expression in vivo. Collectively, we have demonstrated that upregulation of TRAIL and activation of death receptor signaling are pivotal for metformin-induced apoptosis in TNBC and NSCLC cells. Our studies identify a novel mechanism of action of metformin exhibiting potent antitumor activity via induction of endogenous TRAIL.
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Affiliation(s)
- Shuang Liu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong 510095, China.,Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA
| | - Erik V Polsdofer
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Lukun Zhou
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA
| | - Sanbao Ruan
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA
| | - Hui Lyu
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA
| | - Defu Hou
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA
| | - Hao Liu
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA
| | - Ann D Thor
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Zhimin He
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong 510095, China
| | - Bolin Liu
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA
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39
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Zhao H, Swanson KD, Zheng B. Therapeutic Repurposing of Biguanides in Cancer. Trends Cancer 2021; 7:714-730. [PMID: 33865798 DOI: 10.1016/j.trecan.2021.03.001] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 03/05/2021] [Accepted: 03/12/2021] [Indexed: 12/29/2022]
Abstract
Biguanides are a class of antidiabetic drugs that includes phenformin and metformin; however, the former was withdrawn from approval in many countries due to its toxicity. Findings from retrospective epidemiological studies in diabetic populations and preclinical laboratory models have demonstrated that biguanides possess antitumor activities that suggest their repurposing for cancer prevention and treatment. However, a better understanding of how these biguanides behave as antitumor agents is needed to guide their improved applications in cancer therapy, spurring increased interest in their pharmacology. Here, we present evidence for proposed mechanisms of action related to their antitumor activity, including their effects on central carbon metabolism in cancer cells and immune-modulating activity, and then review progress on biguanide repurposing in cancer therapeutics and the possible re-evaluation of phenformin as a cancer therapeutic agent.
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Affiliation(s)
- Hongyun Zhao
- Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Kenneth D Swanson
- Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
| | - Bin Zheng
- Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
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40
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Brancher S, Støer NC, Weiderpass E, Damhuis RAM, Johannesen TB, Botteri E, Strand TE. Metformin use and lung cancer survival: a population-based study in Norway. Br J Cancer 2021; 124:1018-1025. [PMID: 33262518 PMCID: PMC7921644 DOI: 10.1038/s41416-020-01186-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 10/30/2020] [Accepted: 11/05/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND We assessed associations between metformin use and survival in a nationwide Norwegian cohort of lung cancer (LC) patients. METHODS The study linked 22,324 LC patients from the Cancer Registry of Norway diagnosed 2005-2014 with the Norwegian Prescription Database. We estimated associations of pre- and post-diagnostic metformin use with overall survival (OS) and LC-specific survival (LCSS) using multivariable time-fixed and time-dependent Cox regression. RESULTS Pre-diagnostic metformin use was not associated with improved survival in all patients. Nevertheless, pre-diagnostic metformin use was associated with better LCSS in squamous cell carcinoma (SCC) patients (hazard ratio (HR) = 0.79; 95% confidence interval (CI) 0.62-0.99) and in patients with regional stage SCC (HR = 0.67; 95%CI 0.47-0.95). Post-diagnostic metformin use was associated with improved LCSS in all patients (HR = 0.83; 95%CI 0.73-0.95), in patients with SCC (HR = 0.75; 95%CI 0.57-0.98), regional stage LC (HR = 0.74; 95%CI 0.59-0.94), and regional stage SCC (HR = 0.57; 95%CI 0.38-0.86). OS showed similar results. Analyses of cumulative use showed a dose-response relationship in all patients, patients with adenocarcinoma and SCC, and with regional and metastatic LC. CONCLUSIONS Metformin use was associated with improved survival, especially LCSS in patients with regional stage SCC. Further prospective studies are required to clarify the role of metformin in LC treatment.
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MESH Headings
- Adenocarcinoma of Lung/drug therapy
- Adenocarcinoma of Lung/epidemiology
- Adenocarcinoma of Lung/mortality
- Adenocarcinoma of Lung/pathology
- Aged
- Aged, 80 and over
- Carcinoma, Large Cell/drug therapy
- Carcinoma, Large Cell/epidemiology
- Carcinoma, Large Cell/mortality
- Carcinoma, Large Cell/pathology
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/epidemiology
- Carcinoma, Non-Small-Cell Lung/mortality
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Squamous Cell/drug therapy
- Carcinoma, Squamous Cell/epidemiology
- Carcinoma, Squamous Cell/mortality
- Carcinoma, Squamous Cell/pathology
- Combined Modality Therapy
- Female
- Follow-Up Studies
- Humans
- Hypoglycemic Agents/therapeutic use
- Lung Neoplasms/drug therapy
- Lung Neoplasms/epidemiology
- Lung Neoplasms/mortality
- Lung Neoplasms/pathology
- Male
- Metformin/therapeutic use
- Middle Aged
- Norway/epidemiology
- Prognosis
- Small Cell Lung Carcinoma/drug therapy
- Small Cell Lung Carcinoma/epidemiology
- Small Cell Lung Carcinoma/mortality
- Small Cell Lung Carcinoma/pathology
- Survival Rate
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Affiliation(s)
- Suzan Brancher
- Department of Epidemiology, School of Public Health, University of São Paulo, São Paulo, Brazil.
| | - Nathalie C Støer
- Norwegian National Advisory Unit on Women's Health, Women's Clinic, Oslo University Hospital, Oslo, Norway
- Cancer Registry of Norway, Oslo University Hospital, Oslo, Norway
| | - Elisabete Weiderpass
- International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France
| | - Ronald A M Damhuis
- Department of Research, Comprehensive Cancer Organization, Utrecht, The Netherlands
| | - Tom B Johannesen
- Cancer Registry of Norway, Oslo University Hospital, Oslo, Norway
| | - Edoardo Botteri
- Cancer Registry of Norway, Oslo University Hospital, Oslo, Norway
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41
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Mouron S, Bueno MJ, Muñoz M, Quintela-Fandino M. Monitoring vascular normalization: new opportunities for mitochondrial inhibitors in breast cancer. Oncoscience 2021; 8:1-13. [PMID: 33869665 PMCID: PMC8018703 DOI: 10.18632/oncoscience.523] [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: 07/29/2020] [Accepted: 02/08/2021] [Indexed: 11/25/2022] Open
Abstract
Preclinical evidence indicates the potential of targeting mitochondrial respiration as a therapeutic strategy. We previously demonstrated that mitochondrial inhibitors’ efficacy was restricted to a metabolic context in which mitochondrial respiration was the predominant energy source, a situation achievable by inducing vascular normalization/hypoxia correction with antiangiogenics. Using molecular imaging, we showed how the same antiangiogenic agent may display different normalizing properties in patients with the same tumor type. This is of key importance, since patients experiencing normalization seem to get more benefit from standard chemotherapy combinations, and also could be eligible for combination with antimitochondrial agents. This scenario emphasizes the need for monitoring vascular normalization in order to optimize the use of antiangiogenics. We have also proposed a method to evaluate anti-mitochondrial agents’ pharmacodynamics; despite promising accuracy in animal studies the clinical results were inconclusive, highlighting the need for research in this field. Regarding patients that respond to antiangiogenics increasing vessel abnormality, in this case an immunosuppressive tumor microenvironment is generated. Whether anti-mitochondrial agents can positively modulate the activity of T effector cell subpopulations remains an area of active research. Our research sheds light on the importance of refining the use of antiangiogenics, highlighting the relevance of tracing vascular normalization as a potential biomarker for antiangiogenics to assist patient-tailored medicine and exploring the role of mitochondrial inhibitors in the context of vascular normalization and correction of hypoxia.
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Affiliation(s)
- Silvana Mouron
- Breast Cancer Clinical Research Unit - Clinical Research Program, CNIO - Spanish National Cancer Research Center, Madrid, Spain
| | - Maria J Bueno
- Breast Cancer Clinical Research Unit - Clinical Research Program, CNIO - Spanish National Cancer Research Center, Madrid, Spain
| | - Manuel Muñoz
- Breast Cancer Clinical Research Unit - Clinical Research Program, CNIO - Spanish National Cancer Research Center, Madrid, Spain
| | - Miguel Quintela-Fandino
- Breast Cancer Clinical Research Unit - Clinical Research Program, CNIO - Spanish National Cancer Research Center, Madrid, Spain.,Medical Oncology, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain.,Medical Oncology, Hospital Universitario Quiron, Pozuelo de Alarcon, Madrid, Spain.,Department of Medicine, Universidad Autonóma de Madrid, Madrid, Spain
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42
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Saeed HK, Sutar Y, Patel P, Bhat R, Mallick S, Hatada AE, Koomoa DLT, Lange I, Date AA. Synthesis and Characterization of Lipophilic Salts of Metformin to Improve Its Repurposing for Cancer Therapy. ACS OMEGA 2021; 6:2626-2637. [PMID: 33553880 PMCID: PMC7859945 DOI: 10.1021/acsomega.0c04779] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 01/14/2021] [Indexed: 06/12/2023]
Abstract
Epidemiological evidence has accentuated the repurposing of metformin hydrochloride for cancer treatment. However, the extreme hydrophilicity and poor permeability of metformin hydrochloride are responsible for its poor anticancer activity in vitro and in vivo. Here, we report the synthesis and characterization of several lipophilic metformin salts containing bulky anionic permeation enhancers such as caprate, laurate, oleate, cholate, and docusate as counterions. Of various counterions tested, only docusate was able to significantly improve the lipophilicity and lipid solubility of metformin. To evaluate the impact of the association of anionic permeation enhancers with metformin, we checked the in vitro anticancer activity of various lipophilic salts of metformin using drug-sensitive (MYCN-2) and drug-resistant (SK-N-Be2c) neuroblastoma cells as model cancer cells. Metformin hydrochloride showed a very low potency (IC50 ≈ >100 mM) against MYCN-2 and SK-N-Be2c cells. Anionic permeation enhancers showed a considerably higher activity (IC50 ≈ 125 μM to 1.6 mM) against MYCN-2 and SK-N-Be2c cells than metformin. The association of metformin with most of the bulky anionic agents negatively impacted the anticancer activity against MYCN-2 and SK-N-Be2c cells. However, metformin docusate showed 700- to 4300-fold improvement in anticancer potency compared to metformin hydrochloride and four- to five-fold higher in vitro anticancer activity compared to sodium docusate, indicating a synergistic association between metformin and docusate. A similar trend was observed when we tested the in vitro activity of metformin docusate, sodium docusate, and metformin hydrochloride against hepatocellular carcinoma (HepG2) and triple-negative breast cancer (MDA-MB-231) cells.
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Affiliation(s)
- Hiwa K. Saeed
- Department
of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai’i at Hilo, Hilo Hawaii 96720, United States
| | - Yogesh Sutar
- Department
of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai’i at Hilo, Hilo Hawaii 96720, United States
| | - Pratikkumar Patel
- Department
of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai’i at Hilo, Hilo Hawaii 96720, United States
| | - Roopal Bhat
- Department
of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai’i at Hilo, Hilo Hawaii 96720, United States
- Department
of Pharmaceutics, Shree Chanakya Education
Society’s Indira College of Pharmacy, Tathawade, Pune, Maharashtra 411033, India
| | - Sudipta Mallick
- Department
of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai’i at Hilo, Hilo Hawaii 96720, United States
| | - Alyssa E. Hatada
- Department
of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai’i at Hilo, Hilo Hawaii 96720, United States
| | - Dana-Lynn T. Koomoa
- Department
of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai’i at Hilo, Hilo Hawaii 96720, United States
| | - Ingo Lange
- Department
of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai’i at Hilo, Hilo Hawaii 96720, United States
| | - Abhijit A. Date
- Department
of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai’i at Hilo, Hilo Hawaii 96720, United States
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43
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Tsogas FK, Majerczyk D, Hart PC. Possible Role of Metformin as an Immune Modulator in the Tumor Microenvironment of Ovarian Cancer. Int J Mol Sci 2021; 22:ijms22020867. [PMID: 33467127 PMCID: PMC7830067 DOI: 10.3390/ijms22020867] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 01/13/2021] [Indexed: 12/14/2022] Open
Abstract
Growing evidence suggests that the immune component of the tumor microenvironment (TME) may be highly involved in the progression of high-grade serous ovarian cancer (HGSOC), as an immunosuppressive TME is associated with worse patient outcomes. Due to the poor prognosis of HGSOC, new therapeutic strategies targeting the TME may provide a potential path forward for preventing disease progression to improve patient survival. One such postulated approach is the repurposing of the type 2 diabetes medication, metformin, which has shown promise in reducing HGSOC tumor progression in retrospective epidemiological analyses and through numerous preclinical studies. Despite its potential utility in treating HGSOC, and that the immune TME is considered as a key factor in the disease’s progression, little data has definitively shown the ability of metformin to target this component of the TME. In this brief review, we provide a summary of the current understanding of the effects of metformin on leukocyte function in ovarian cancer and, coupled with data from other related disease states, posit the potential mechanisms by which the drug may enhance the anti-tumorigenic effects of immune cells to improve HGSOC patient survival.
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Affiliation(s)
- Faye K. Tsogas
- College of Science, Health and Pharmacy, Roosevelt University, Schaumburg, IL 60173, USA; (F.K.T.); (D.M.)
| | - Daniel Majerczyk
- College of Science, Health and Pharmacy, Roosevelt University, Schaumburg, IL 60173, USA; (F.K.T.); (D.M.)
- Loyola Medicine, Berwyn, IL 60402, USA
| | - Peter C. Hart
- College of Science, Health and Pharmacy, Roosevelt University, Schaumburg, IL 60173, USA; (F.K.T.); (D.M.)
- Correspondence:
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Tang Z, Tang N, Jiang S, Bai Y, Guan C, Zhang W, Fan S, Huang Y, Lin H, Ying Y. The Chemosensitizing Role of Metformin in Anti-Cancer Therapy. Anticancer Agents Med Chem 2021; 21:949-962. [PMID: 32951587 DOI: 10.2174/1871520620666200918102642] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/23/2020] [Accepted: 08/08/2020] [Indexed: 11/22/2022]
Abstract
Chemoresistance, which leads to the failure of chemotherapy and further tumor recurrence, presents the largest hurdle for the success of anti-cancer therapy. In recent years, metformin, a widely used first-line antidiabetic drug, has attracted increasing attention for its anti-cancer effects. A growing body of evidence indicates that metformin can sensitize tumor responses to different chemotherapeutic drugs, such as hormone modulating drugs, anti-metabolite drugs, antibiotics, and DNA-damaging drugs via selective targeting of Cancer Stem Cells (CSCs), improving the hypoxic microenvironment, and by suppressing tumor metastasis and inflammation. In addition, metformin may regulate metabolic programming, induce apoptosis, reverse Epithelial to Mesenchymal Transition (EMT), and Multidrug Resistance (MDR). In this review, we summarize the chemosensitization effects of metformin and focus primarily on its molecular mechanisms in enhancing the sensitivity of multiple chemotherapeutic drugs, through targeting of mTOR, ERK/P70S6K, NF-κB/HIF-1 α, and Mitogen- Activated Protein Kinase (MAPK) signaling pathways, as well as by down-regulating the expression of CSC genes and Pyruvate Kinase isoenzyme M2 (PKM2). Through a comprehensive understanding of the molecular mechanisms of chemosensitization provided in this review, the rationale for the use of metformin in clinical combination medications can be more systematically and thoroughly explored for wider adoption against numerous cancer types.>.
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Affiliation(s)
- Zhimin Tang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Nan Tang
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330006, China
| | - Shanshan Jiang
- Institute of Hematological Research, Shanxi Provincial People's Hospital, Xian 710000, China
| | - Yangjinming Bai
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330006, China
| | - Chenxi Guan
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Wansi Zhang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Shipan Fan
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou 510005, China
| | - Yonghong Huang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Hui Lin
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Ying Ying
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
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Dowling CM, Zhang H, Chonghaile TN, Wong KK. Shining a light on metabolic vulnerabilities in non-small cell lung cancer. Biochim Biophys Acta Rev Cancer 2021; 1875:188462. [PMID: 33130228 PMCID: PMC7836022 DOI: 10.1016/j.bbcan.2020.188462] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 10/20/2020] [Accepted: 10/24/2020] [Indexed: 12/17/2022]
Abstract
Metabolic reprogramming is a hallmark of cancer which contributes to essential processes required for cell survival, growth, and proliferation. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and its genomic classification has given rise to the design of therapies targeting tumors harboring specific gene alterations that cause aberrant signaling. Lung tumors are characterized with having high glucose and lactate use, and high heterogeneity in their metabolic pathways. Here we review how NSCLC cells with distinct mutations reprogram their metabolic pathways and highlight the potential metabolic vulnerabilities that might lead to the development of novel therapeutic strategies.
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Affiliation(s)
- Catríona M Dowling
- Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA; School of Medicine, University of Limerick, Limerick, Ireland
| | - Hua Zhang
- Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
| | - Tríona Ní Chonghaile
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Kwok-Kin Wong
- Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
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Zhang M, Chen X, Radacsi N. New tricks of old drugs: Repurposing non-chemo drugs and dietary phytochemicals as adjuvants in anti-tumor therapies. J Control Release 2020; 329:96-120. [PMID: 33259852 DOI: 10.1016/j.jconrel.2020.11.047] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/22/2020] [Accepted: 11/24/2020] [Indexed: 12/14/2022]
Abstract
Combination therapy has long been applied to enhance therapeutic effect and deal with the occurrence of multi-drug resistance in cancer treatment. However, the overlapping toxicity of multiple anticancer drugs to healthy tissues and increasing financial burden on patients emerged as major concerns. As promising alternatives to chemo agents, repurposed non-chemo drugs and dietary phytochemicals have been investigated as adjuvants to conventional anti-tumor therapeutics, offering a safe and economic strategy for combination therapy. In this review, we aim to highlight the advances in research about combination therapy using conventional therapeutics and repurposed drugs or phytochemicals for an enhanced anti-tumor efficacy, along with the mechanisms involved in the synergism. Beyond these, we outlined the potential challenges and solutions for clinical translation of the proposed combination therapy, providing a safe and affordable strategy to improve the reach of cancer therapy to low income regions with such new tricks of old drugs.
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Affiliation(s)
- Mei Zhang
- School of Engineering, Institute for Materials and Processes, University of Edinburgh, Robert Stevenson Road, Edinburgh EH9 3FB, United Kingdom; School of Engineering, Institute for Bioengineering, University of Edinburgh, The King's Buildings, Edinburgh EH9 3JL, United Kingdom.
| | - Xianfeng Chen
- School of Engineering, Institute for Bioengineering, University of Edinburgh, The King's Buildings, Edinburgh EH9 3JL, United Kingdom.
| | - Norbert Radacsi
- School of Engineering, Institute for Materials and Processes, University of Edinburgh, Robert Stevenson Road, Edinburgh EH9 3FB, United Kingdom.
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Wu Z, Qu B, Huang X, Song Y, Gao P, Shi J, Zhou C, Wang Z. The potential adjunctive benefit of adding metformin to standard treatment in inoperable cancer patients: a meta-analysis of randomized controlled trials. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1404. [PMID: 33313149 PMCID: PMC7723600 DOI: 10.21037/atm-20-4441] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Recently, there have been several randomized clinical trials (RCTs) conducted to evaluate the efficacy and safety of metformin plus standard treatment in inoperable cancer patients. Our meta-analysis aimed to assess the efficacy of metformin in combination with standard treatment in inoperable cancer patients. Methods PubMed and Embase databases were systematically searched for relevant RCTs investigating the efficacy of adding metformin to standard treatment for cancer patients. The pooled relative risk (RR) for tumor response and safety was calculated to assess the efficacy of combining metformin with standard treatment. Meta-analysis was subsequently performed to pool the hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). Results Ten RCTs comprising 1033 patients were included in our current meta-analysis. In patients with breast cancer, results of meta-analysis showed that the addition of metformin to standard treatment was beneficial to objective response rate (ORR) with 30.3% (33/109) in the metformin plus standard treatment group and 16.1% (18/112) in the placebo group (RR 1.92, 95% CI: 1.19–3.10, P=0.008). OS and PFS were not significantly improved in patients who received metformin plus standard treatment compared with those who received placebo plus standard treatment (OS: HR 1.02, 95% CI: 0.71–1.46, P=0.916; PFS: HR 1.14, 95% CI: 0.86–1.50, P=0.366). For lung cancer patients, meta-analysis results showed adding metformin to standard treatment could benefit ORR (metformin 65.3% vs. placebo 54.6%, RR 1.22, 95% CI: 1.03–1.43, P=0.018) with no significant survival benefit in the metformin group. For patients with pancreatic cancer, the pooled ORR was 17.6% (16/91) in metformin plus standard treatment group and 20% (18/90) in the placebo group, indicating metformin did not benefit ORR (RR 0.85, 95% CI: 0.49–1.49, P=0.576). Besides, the addition of metformin to standard treatment did not increase the incidence rate of adverse effects. Conclusions Our results indicated that addition of metformin to standard treatment was beneficial to ORR in inoperable breast or lung cancer patients without increasing the incidence of adverse effects. However, adding metformin to standard treatment could not benefit OS and PFS.
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Affiliation(s)
- Zhonghua Wu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Bicheng Qu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xuanzhang Huang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Peng Gao
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jinxin Shi
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Cen Zhou
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
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Broekman KE, Hof MAJ, Touw DJ, Gietema JA, Nijman HW, Lefrandt JD, Reyners AKL, Jalving M. Phase I study of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced epithelial ovarian cancer. Invest New Drugs 2020; 38:1454-1462. [PMID: 32146550 PMCID: PMC7497683 DOI: 10.1007/s10637-020-00920-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 02/28/2020] [Indexed: 12/24/2022]
Abstract
Background Metformin use is associated with reduced cancer risk in epidemiological studies and has preclinical anti-cancer activity in ovarian cancer models. The primary objective of this phase I study was to determine the recommended phase II dose (RP2D) of metformin in combination with carboplatin/paclitaxel in patients with ovarian cancer. Secondary objectives were to describe safety and pharmacokinetics. Methods In this single-center trial the RP2D of metformin in combination with carboplatin area under the concentration-time curve (AUC) 6 and paclitaxel 175 mg/m2 every 3 weeks (q3w) in patients with advanced epithelial ovarian cancer was determined using a 3 + 3 escalation rule at three fixed dose levels: 500 mg three times daily (tds), 850 mg tds and 1000 mg tds. Metformin was commenced on day 3 of cycle 1 and continued until 3 weeks after the last chemotherapy administration. The RP2D was defined as the dose level at which 0 of 3 or ≤ 1 of 6 evaluable subjects experienced a metformin-related dose-limiting toxicity (DLT). Safety was assessed according to CTCAE v4.0. Plasma and serum samples for pharmacokinetic (PK) analyses were collected during treatment cycles 1 and 2. Results Fifteen patients with epithelial ovarian cancer and an indication for neo-adjuvant (n = 5) or palliative (n = 10) treatment were included. No DLTs were observed. Three patients discontinued study treatment during cycle 1 for other reasons than DLT. Six patients were treated at the RP2D of metformin 1000 mg tds. The most frequent low-grade toxicities were anemia, hypomagnesemia and diarrhea. Grade 3 adverse events (AEs) occurred in ten patients, most common were leucopenia (n = 4), thrombocytopenia (n = 3) and increased GGT (n = 3). There were no grade 4 AEs. Metformin increased the platinum (Pt) AUC (Δ22%, p = 0.013) and decreased the Pt clearance (Δ-28%, p = 0.013). Metformin plasma levels were all within the therapeutic range for diabetic patients (0.1-4 mg/L). Conclusion The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000 mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified.
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Affiliation(s)
- K Esther Broekman
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands
| | - Marieke A J Hof
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Daan J Touw
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Jourik A Gietema
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands
| | - Hans W Nijman
- Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Joop D Lefrandt
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - An K L Reyners
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands
| | - Mathilde Jalving
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands.
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Chen YC, Li H, Wang J. Mechanisms of metformin inhibiting cancer invasion and migration. Am J Transl Res 2020; 12:4885-4901. [PMID: 33042396 PMCID: PMC7540116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 08/01/2020] [Indexed: 06/11/2023]
Abstract
Cancer currently ranks among the leading causes of death globally. Cancer invasion and metastasis transform locally grown cancers to a systemic and life-threatening disease, which accounts for the most significant challenge in cancer treatment. Recent studies showed that Metformin, the most commonly used first-line oral drug for the treatment of type 2 diabetes (T2DM), could prevent and treat various cancers. Moreover, multiple evidence suggested that metformin inhibited cancer invasion and metastasis, which could improve the prognosis of cancer patients administrated with metformin. To better understand the anti-cancer role of metformin, the present review summarized the potential mechanisms of inhibiting cancer invasion and metastasis by metformin, including AMPK signaling pathway, EMT signaling pathway, epigenetic modification and so on. However, multiple problems remain unresolved and more clinical trials are needed to prove the inhibition of cancer invasion and metastasis by metformin.
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Affiliation(s)
- Yong Chang Chen
- Gynecologic Oncology Clinical Research Center, Hunan Cancer Hospital, Central South UniversityChangsha 410013, Hunan, China
- University of South ChinaHengyang 421001, Hunan, China
| | - He Li
- Gynecologic Oncology Clinical Research Center, Hunan Cancer Hospital, Central South UniversityChangsha 410013, Hunan, China
| | - Jing Wang
- Gynecologic Oncology Clinical Research Center, Hunan Cancer Hospital, Central South UniversityChangsha 410013, Hunan, China
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