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Vázquez-Ibarra KC, Sánchez López JY, Pineda Razo TD, Cruz Lozano JR, Ortiz-Tamayo BG, Palafox-Mariscal LA, González Arreola RM, González-García JR, Ortiz-Lazareno PC. Metformin in combination with chemotherapy increases apoptosis in gastric cancer cells and counteracts senescence induced by chemotherapy. Oncol Lett 2024; 28:457. [PMID: 39114572 PMCID: PMC11304395 DOI: 10.3892/ol.2024.14590] [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: 02/11/2024] [Accepted: 06/10/2024] [Indexed: 08/10/2024] Open
Abstract
Gastric cancer (GC) is the fourth leading cause of cancer death in the world, and there is a demand for new therapeutic agents to treat GC. Metformin has been demonstrated to be an antineoplastic agent in some types of cancer; however, it has not been sufficiently valued in treating GC because the effect of metformin in combination with chemotherapy regimens has not yet been evaluated. The present study aimed to evaluate the mechanisms underlying cell death induced by metformin alone or when combined with chemotherapy. The cytogenetic characteristics of the NCI-N87 cell line were determined by fluorescence in situ hybridization (FISH). To determine viability, the cells were treated with metformin, epirubicin, cisplatin, docetaxel and 5-fluorouracil (individually and at different concentrations). Subsequently, the cells were treated with metformin alone, and in combination with the chemotherapeutic drugs and the epirubicin + cisplatin + 5-fluorouracil, docetaxel + cisplatin + 5-fluorouracil, and cisplatin + 5-fluorouracil regimens. Cell viability, proliferation and mitochondrial membrane potential (ΔΨm) were analyzed by spectrophotometry. Apoptosis, caspase activity and cell cycle progression were assessed by flow cytometry. Finally, light microscopy was used to evaluate senescence and clonogenicity. The results revealed that metformin, alone and when combined with chemotherapy, increased the proportion of apoptotic cells, promoted the loss of ΔΨm, and induced apoptosis through caspase activity in GC cells. Moreover, metformin decreased cell proliferation. In addition, metformin alone did not induce senescence and it counteracted the effects of chemotherapy-induced senescence in GC cells. Additionally, metformin, alone and when combined with chemotherapy, decreased the clonogenic capacity of NCI-N87 GC cells. In conclusion, metformin may increase the effects of chemotherapy on NCI-N87 cell death and could represent an option to improve the treatment of GC.
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Affiliation(s)
- Katia Carolina Vázquez-Ibarra
- Department of Molecular Biology and Genomics, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Josefina Yoaly Sánchez López
- Genetic Division, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco, 44340, Mexico
| | - Tomás Daniel Pineda Razo
- Medical Oncology Service, Western National Medical Center, Mexican Social Security Institute, Guadalajara, Jalisco 44329, Mexico
| | - José Roberto Cruz Lozano
- Department of Physiology, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Brenda Guadalupe Ortiz-Tamayo
- Division of Biological and Environmental Sciences, University Center of Biological and Agricultural Sciences, University of Guadalajara, Guadalajara, Jalisco 44600, Mexico
| | - Luis Arturo Palafox-Mariscal
- Department of Physiology, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Rosa María González Arreola
- Department of Molecular Biology and Genomics, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Juan Ramón González-García
- Genetic Division, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco, 44340, Mexico
| | - Pablo Cesar Ortiz-Lazareno
- Immunology Division, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
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Deng H, Qian X, Zhang Y, Yu W, Yang P. Metformin Increases the Response of Cholangiocarcinoma Cells to Gemcitabine by Suppressing Pyruvate Kinase M2 to Activate Mitochondrial Apoptosis. Dig Dis Sci 2024; 69:476-490. [PMID: 38170336 DOI: 10.1007/s10620-023-08210-x] [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: 04/16/2023] [Accepted: 11/24/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is a malignant tumor with a high mortality rate. Resistance to chemotherapy remains a major challenge related to cancer treatment, and increasing the sensitivity of cancer cells to therapeutic drugs is a major focus of cancer treatment. AIMS We purposed to explore the role of Metformin in CCA involved in chemotherapeutic sensitivity and Pyruvate kinase M2 (PKM2) through regulating mitochondrial apoptosis in the present study. METHODS CCA cell lines of HCC9810 and RBE were treated with Metformin companied with antagonists or agonists of PKM2, cells sensitivity to Gemcitabine, cell migration and invasion along with apoptosis, which is mediated by JC-1 and LDH were assayed. RESULTS Our results indicated that Metformin and Gemcitabine exhibit synergistic effect on inhibition of cholangiocarcinoma cell viability, cell migration and invasion as well as promotion apoptosis of cholangiocarcinoma cells. In vivo, Metformin combined with Gemcitabine has cooperation in inhibiting the growth of cholangiocarcinoma cell-derived tumors. Moreover, Metformin and Gemcitabine inhibited expression of PKM2 and PDHB in HCC9810 and RBE. CONCLUSION Our study suggested that Metformin may increase the response of cholangiocarcinoma cells to Gemcitabine by suppressing PKM2 to activate mitochondrial apoptosis.
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Affiliation(s)
- Haishan Deng
- Department of General Surgery, Armed Police Coast Guard Corps Hospital, Jiaxing, Zhejiang, China
| | - Xiaomei Qian
- Jiaxing Shuguang Cosmetology Hospital, Jiaxing, Zhejiang, China
| | - Yongtao Zhang
- Department of General Surgery, Armed Police Coast Guard Corps Hospital, Jiaxing, Zhejiang, China
| | - Wenlong Yu
- The Second Department of Biliary Duct, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Ping Yang
- Department of Radiotherapy, The First Affiliated Hospital of Hainan Medical University, No. 31 Longhua Road, Haikou, 570102, Hainan, China.
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Franco-Juárez EX, González-Villasana V, Camacho-Moll ME, Rendón-Garlant L, Ramírez-Flores PN, Silva-Ramírez B, Peñuelas-Urquides K, Cabello-Ruiz ED, Castorena-Torres F, Bermúdez de León M. Mechanistic Insights about Sorafenib-, Valproic Acid- and Metformin-Induced Cell Death in Hepatocellular Carcinoma. Int J Mol Sci 2024; 25:1760. [PMID: 38339037 PMCID: PMC10855535 DOI: 10.3390/ijms25031760] [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: 10/09/2023] [Revised: 12/12/2023] [Accepted: 12/13/2023] [Indexed: 02/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is among the main causes of death by cancer worldwide, representing about 80-90% of all liver cancers. Treatments available for advanced HCC include atezolizumab, bevacizumab, sorafenib, among others. Atezolizumab and bevacizumab are immunological options recently incorporated into first-line treatments, along with sorafenib, for which great treatment achievements have been reached. However, sorafenib resistance is developed in most patients, and therapeutical combinations targeting cancer hallmark mechanisms and intracellular signaling have been proposed. In this review, we compiled evidence of the mechanisms of cell death caused by sorafenib administered alone or in combination with valproic acid and metformin and discussed them from a molecular perspective.
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Affiliation(s)
- Edgar Xchel Franco-Juárez
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey 64720, Nuevo Leon, Mexico; (E.X.F.-J.); (M.E.C.-M.); (P.N.R.-F.); (K.P.-U.)
- Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza 66451, Nuevo Leon, Mexico; (V.G.-V.); (L.R.-G.); (E.D.C.-R.)
| | - Vianey González-Villasana
- Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza 66451, Nuevo Leon, Mexico; (V.G.-V.); (L.R.-G.); (E.D.C.-R.)
| | - María Elena Camacho-Moll
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey 64720, Nuevo Leon, Mexico; (E.X.F.-J.); (M.E.C.-M.); (P.N.R.-F.); (K.P.-U.)
| | - Luisa Rendón-Garlant
- Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza 66451, Nuevo Leon, Mexico; (V.G.-V.); (L.R.-G.); (E.D.C.-R.)
| | - Patricia Nefertari Ramírez-Flores
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey 64720, Nuevo Leon, Mexico; (E.X.F.-J.); (M.E.C.-M.); (P.N.R.-F.); (K.P.-U.)
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Nuevo Leon, Mexico;
| | - Beatriz Silva-Ramírez
- Departamento de Inmunogenética, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey 64720, Nuevo Leon, Mexico;
| | - Katia Peñuelas-Urquides
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey 64720, Nuevo Leon, Mexico; (E.X.F.-J.); (M.E.C.-M.); (P.N.R.-F.); (K.P.-U.)
| | - Ethel Daniela Cabello-Ruiz
- Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza 66451, Nuevo Leon, Mexico; (V.G.-V.); (L.R.-G.); (E.D.C.-R.)
| | - Fabiola Castorena-Torres
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Nuevo Leon, Mexico;
| | - Mario Bermúdez de León
- Departamento de Biología Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey 64720, Nuevo Leon, Mexico; (E.X.F.-J.); (M.E.C.-M.); (P.N.R.-F.); (K.P.-U.)
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Kim JS, Kim MY, Hong S. Synergistic Effects of Metformin and Trastuzumab on HER2 Positive Gastroesophageal Adenocarcinoma Cells In Vitro and In Vivo. Cancers (Basel) 2023; 15:4768. [PMID: 37835462 PMCID: PMC10571931 DOI: 10.3390/cancers15194768] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/16/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
The incidence of HER2 amplification in advanced gastroesophageal adenocarcinoma (GC) reportedly ranges between 10% and 20%, depending on the population studied and the geographical region. Trastuzumab (Tmab) is the standard treatment for GCs with HER2 amplification. Metformin, a widely used antidiabetic drug, is an activator of AMP kinase that can affect the mTOR signaling pathway. The following GC cells were evaluated: HER2+ NCI-N87, YCC-19, YCC-38, OE19, OE33, and HER2- AGS. The effects of Tmab and metformin on these cell lines were assessed as single agents and in combination using cell viability assays, Western blotting, and xenograft models. Metformin induced phosphorylation of AMP kinase in all tested GC cells and dephosphorylation of mTOR in Tmab-sensitive GC cells. We observed that treatment with Tmab in combination with metformin induced a significant decrease in the number of colonies formed on soft agar by N87, YCC-19, YCC-38, and OE19 cells (88%, 95%, 73%, and 98%, respectively), in comparison to the number formed by control cells or cells in the single-treatment groups. No growth inhibition was detected in OE33 cells treated with Tmab alone. Combination with metformin resulted in decreased phosphorylation of HER2 and its downstream targets, AKT and ERK, in Tmab-sensitive HER2+ cells. Phospho-receptor tyrosine kinase (RTK) arrays were used to profile the phospho-proteome, which demonstrated a synergistic decrease in phosphorylation of EGFR, HER2, and HER3. Furthermore, the combination of Tmab and metformin exhibited enhanced antitumor effects in a xenograft model. Collectively, these data suggest that Tmab and metformin act synergistically in HER2+ GC cells. Since metformin is widely used and relatively non-toxic, its addition to the therapeutic regimen along with Tmab could enhance the clinical efficacy in patients with HER2+ GC.
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Affiliation(s)
- Jin-Soo Kim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea;
| | - Mi Young Kim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea;
| | - Sungyoul Hong
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea;
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Zhang Y, Gao Z, Pan Z, Fu H, Jiang F, Yan H, Yang B, He Q, Luo P, Xu Z, Yang X. Crizotinib induces pulmonary toxicity by blocking autophagy flux in alveolar epithelial cells. Biochem Pharmacol 2023; 215:115636. [PMID: 37290598 DOI: 10.1016/j.bcp.2023.115636] [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: 02/03/2023] [Revised: 05/29/2023] [Accepted: 05/31/2023] [Indexed: 06/10/2023]
Abstract
Crizotinib is the first-line drug for advanced non-small cell lung cancer with the abnormal expression of anaplastic lymphoma kinase gene. Severe, life-threatening, or fatal interstitial lung disease/pneumonia has been reported in patients treated with crizotinib. The clinical benefit of crizotinib is limited by its pulmonary toxicity, but the underlying mechanisms have not been adequately studied, and protective strategies are relatively scarce. Here, we established an in vivo mouse model in which crizotinib was continuously administered to C57BL/6 at 100 mg/kg/day for 6 weeks and verified that crizotinib induced interstitial lung disease in vivo, which was consistent with the clinical observations. We further treated BEAS-2B and TC-1 cells, the alveolar epithelial cell lines, with crizotinib and found the increased apoptosis rate. We proved that crizotinib-blocked autophagic flux caused apoptosis of the alveolar epithelial cells and then promoted the recruitment of immune cells, suggesting that limited autophagy activity was the key reason for pulmonary injury and inflammation caused by crizotinib. Subsequently, we found that metformin could reduce the macrophage recruitment and pulmonary fibrosis by recovering the autophagy flux, thereby ameliorating impaired lung function caused by crizotinib. In conclusion, our study revealed the mechanism of crizotinib-induced apoptosis of alveolar epithelial cells and activation of inflammation during the onset of pulmonary toxicity and provided a promising therapeutic strategy for the treatment of crizotinib-induced pulmonary toxicity.
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Affiliation(s)
- Yuanteng Zhang
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China; Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Zizheng Gao
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Zezheng Pan
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Huangxi Fu
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Feng Jiang
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Hao Yan
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Bo Yang
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Qiaojun He
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, Zhejiang, China; Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Peihua Luo
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Zhifei Xu
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
| | - Xiaochun Yang
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
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Wang X, Wang H, Yi P, Baker C, Casey G, Xie X, Luo H, Cai J, Fan X, Soong L, Hu H, Shi PY, Liang Y, Sun J. Metformin restrains ZIKV replication and alleviates virus-induced inflammatory responses in microglia. Int Immunopharmacol 2023; 121:110512. [PMID: 37343373 DOI: 10.1016/j.intimp.2023.110512] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/05/2023] [Accepted: 06/12/2023] [Indexed: 06/23/2023]
Abstract
The re-emergence of Zika virus (ZIKV) remains a major public health threat that has raised worldwide attention. Accumulating evidence suggests that ZIKV can cause serious pathological changes to the human nervous system, including microcephaly in newborns. Recent studies suggest that metformin, an established treatment for diabetes may play a role in viral infection; however, little is known about the interactions between ZIKV infection and metformin administration. Using fluorescent ZIKV by flow cytometry and immunofluorescence imaging, we found that ZIKV can infect microglia in a dose-dependent manner. Metformin diminished ZIKV replication without the alteration of viral entry and phagocytosis. Our study demonstrated that metformin downregulated ZIKV-induced inflammatory response in microglia in a time- and dose-dependent manner. Our RNA-Seq and qRT-PCR analysis found that type I and III interferons (IFN), such as IFNα2, IFNβ1 and IFNλ3 were upregulated in ZIKV-infected cells by metformin treatment, accompanied with the downregulation of GBP4, OAS1, MX1 and ISG15. Together, our results suggest that metformin-mediated modulation in multiple pathways may attribute to restraining ZIKV infection in microglia, which may provide a potential tool to consider for use in unique clinical circumstances.
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Affiliation(s)
- Xiaofang Wang
- Department of Infectious Disease, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan 410005, China; Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Hui Wang
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Panpan Yi
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Coleman Baker
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Gonzales Casey
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Xuping Xie
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Huanle Luo
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Jiyang Cai
- Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Xuegong Fan
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Lynn Soong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Haitao Hu
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Pei-Yong Shi
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA; Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Yuejin Liang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.
| | - Jiaren Sun
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.
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Zhang LY, Yin YH, Wang XJ. Advances in the mechanism of action of metformin in pituitary tumors. World J Meta-Anal 2023; 11:144-150. [DOI: 10.13105/wjma.v11.i5.144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/20/2023] [Accepted: 04/14/2023] [Indexed: 06/16/2023] Open
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Rosidi B, Priyatno D, Putra TP, Yusuf I. Metformin Induces a Caspase 3-Unrelated Apoptosis in Human Colorectal Cancer Cell Lines HCT116 and SW620. Cancer Manag Res 2023; 15:475-485. [PMID: 37312884 PMCID: PMC10259592 DOI: 10.2147/cmar.s385278] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 03/16/2023] [Indexed: 06/15/2023] Open
Abstract
Purpose To study the effects of metformin on the proliferation and growth of human colorectal cancer cell lines HCT116 and SW620. Materials and Methods The antiproliferative effect of metformin was assayed using an MTS reagent and its ability to inhibit colony formation was demonstrated using a clonogenic assay. Flow cytometry using YO-PRO-1/PI was performed to examine the effects of metformin on apoptosis and cell death of HCT116 and SW620. Caspase 3 activities were measured in caspase-3 activity tests using a caspase-3 activity kit. Furthermore, Western blots were performed with anti-PARP1, anti-caspase 3, and anti-cleaved caspase 3 to confirm whether caspase activation was present or not. Results Both MTS proliferation assays and clonogenic assays showed that metformin inhibited the proliferation and growth of HCT116 and SW620 cells in a concentration-dependent manner. Flow cytometric analysis identified early apoptosis and metformin-induced cell death in both cell lines. However, caspase 3 activity could not be detected. Cleavage of both PARP1 and pro-caspase 3 was not observed in the Western blot, confirming the absence of caspase 3 activations. Conclusion This present study suggests a caspase 3-unrelated apoptosis mechanism of metformin-induced cell death in human colorectal cancer cell lines HCT116 and SW620.
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Affiliation(s)
- Bustanur Rosidi
- Division of Proteomics, Mochtar Riady Institute for Nanotechnology and Medical Science Group, University of Pelita Harapan, Tangerang, Banten, Indonesia
| | - Diana Priyatno
- Division of Proteomics, Mochtar Riady Institute for Nanotechnology and Medical Science Group, University of Pelita Harapan, Tangerang, Banten, Indonesia
| | - Teguh Pribadi Putra
- Division of Proteomics, Mochtar Riady Institute for Nanotechnology and Medical Science Group, University of Pelita Harapan, Tangerang, Banten, Indonesia
| | - Irawan Yusuf
- Division of Proteomics, Mochtar Riady Institute for Nanotechnology and Medical Science Group, University of Pelita Harapan, Tangerang, Banten, Indonesia
- Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
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Fatehi R, Rashedinia M, Akbarizadeh AR, Zamani M, Firouzabadi N. Metformin enhances anti-cancer properties of resveratrol in MCF-7 breast cancer cells via induction of apoptosis, autophagy and alteration in cell cycle distribution. Biochem Biophys Res Commun 2023; 644:130-139. [PMID: 36641965 DOI: 10.1016/j.bbrc.2022.12.069] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 11/26/2022] [Accepted: 12/22/2022] [Indexed: 12/25/2022]
Abstract
Breast cancer is the fifth leading cause of death, worldwide affecting both genders. Accumulating evidence suggests that metformin, an oral hypoglycemic agent used in the management of type 2 diabetes, exerts anti-tumor effects in many cancers, including the breast cancer. Resveratrol, a natural product found abundantly in many fruits, exhibits marked cytotoxic and pro-oxidant effects. This study was designed to investigate the effect of metformin in combination with resveratrol and cisplatin in MCF-7 cells. Study groups were as follows: untreated control group, single treatment groups (metformin, resveratrol, and cisplatin), double treatment groups (metformin + resveratrol, metformin + cisplatin, and cisplatin + resveratrol) and triple treatment groups (metformin + resveratrol + cisplatin). Our results indicated that metformin inhibits proliferation of MCF-7 cells, an effect that was associated with ROS production and G0/G1 cell cycle arrest, but not apoptosis. Moreover, resveratrol suppressed the proliferation of MCF-7 cells by induction of apoptosis as well as cell cycle arrest. Notably, a significant inhibitory effect in the co-treatment of metformin, resveratrol, and cisplatin was observed which was attributed to induction of autophagy-mediated cell death and apoptosis along cell cycle arrest. In conclusion, our results advocate the anti-cancer properties of metformin and resveratrol on MCF-7 cell s via induction of cell cycle arrest. Additionally, synergistic anti-cancer effects of metformin in a triple combination with cisplatin and resveratrol was attributed to induction of autophagy-mediated cell death and apoptosis along cell cycle arrest. Based on our findings it is proposed that patients may benefit from addition of a drug with a safe profile to conventional anticancer therapies.
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Affiliation(s)
- Reihaneh Fatehi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Marzieh Rashedinia
- Food and Supplements Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amin Reza Akbarizadeh
- Department of Quality Control, Food and Drug, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mozhdeh Zamani
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Firouzabadi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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Wu XY, Xu WW, Huan XK, Wu GN, Li G, Zhou YH, Najafi M. Mechanisms of cancer cell killing by metformin: a review on different cell death pathways. Mol Cell Biochem 2023; 478:197-214. [PMID: 35771397 DOI: 10.1007/s11010-022-04502-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 06/08/2022] [Indexed: 01/17/2023]
Abstract
Cancer resistance to anti-tumour agents has been one of the serious challenges in different types of cancer treatment. Usually, an increase in the cell death markers can predict a higher rate of survival among patients diagnosed with cancer. By increasing the regulation of survival genes, cancer cells can display a higher resistance to therapy through the suppression of anti-tumour immunity and inhibition of cell death signalling pathways. Administration of certain adjuvants may be useful in order to increase the therapeutic efficiency of anti-cancer therapy through the stimulation of different cell death pathways. Several studies have demonstrated that metformin, an antidiabetic drug with anti-cancer properties, amplifies cell death mechanisms, especially apoptosis in a broad-spectrum of cancer cells. Stimulation of the immune system by metformin has been shown to play a key role in the induction of cell death. It seems that the induction or suppression of different cell death mechanisms has a pivotal role in either sensitization or resistance of cancer cells to therapy. This review explains the cellular and molecular mechanisms of cell death following anticancer therapy. Then, we discuss the modulatory roles of metformin on different cancer cell death pathways including apoptosis, mitotic catastrophe, senescence, autophagy, ferroptosis and pyroptosis.
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Affiliation(s)
- Xiao-Yu Wu
- Department of Surgical Oncology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Wen-Wen Xu
- Department of Gynaecology, The Affiliated Hospital of Nanjing University of Chinese Medi-Cine, Nanjing, 210029, Jiangsu, China
| | - Xiang-Kun Huan
- Department of Surgical Oncology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Guan-Nan Wu
- Department of Surgical Oncology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Gang Li
- Department of General Surgery, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
| | - Yu-Hong Zhou
- Digestive Endoscopy Center, The Affiliated Hospital of Nanjing University of Chinese Medi-Cine, Nanjing, 210029, Jiangsu, China.
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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11
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Leite M, Seruca R, Gonçalves JM. Drug Repurposing in Gastric Cancer: Current Status and Future Perspectives. HEREDITARY GASTRIC AND BREAST CANCER SYNDROME 2023:281-320. [DOI: 10.1007/978-3-031-21317-5_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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12
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Sanati M, Aminyavari S, Mollazadeh H, Motamed-Sanaye A, Bibak B, Mohtashami E, Teng Y, Afshari AR, Sahebkar A. The Potential Therapeutic Impact of Metformin in Glioblastoma Multiforme. Curr Med Chem 2023; 30:857-877. [PMID: 35796457 DOI: 10.2174/0929867329666220707103525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 03/13/2022] [Accepted: 04/16/2022] [Indexed: 02/08/2023]
Abstract
In terms of frequency and aggressiveness, glioblastoma multiforme (GBM) is undoubtedly the most frequent and fatal primary brain tumor. Despite advances in clinical management, the response to current treatments is dismal, with a 2-year survival rate varying between 6 and 12 percent. Metformin, a derivative of biguanide widely used in treating type 2 diabetes, has been shown to extend the lifespan of patients with various malignancies. There is limited evidence available on the long-term survival of GBM patients who have taken metformin. This research examined the literature to assess the connection between metformin's anticancer properties and GBM development. Clinical findings, together with the preclinical data from animal models and cell lines, are included in the present review. This comprehensive review covers not only the association of hyperactivation of the AMPK pathway with the anticancer activity of metformin but also other mechanisms underpinning its role in apoptosis, cell proliferation, metastasis, as well as its chemo-radio-sensitizing behavior against GBM. Current challenges and future directions for developments and applications of metformin-based therapeutics are also discussed.
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Affiliation(s)
- Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Samaneh Aminyavari
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Mollazadeh
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Ali Motamed-Sanaye
- Student Research Committee, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Bahram Bibak
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Elmira Mohtashami
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yong Teng
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA30322, USA
| | - Amir R Afshari
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Medicine, The University of Western Australia, Perth, Australia
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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13
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Araújo D, Ribeiro E, Amorim I, Vale N. Repurposed Drugs in Gastric Cancer. MOLECULES (BASEL, SWITZERLAND) 2022; 28:molecules28010319. [PMID: 36615513 PMCID: PMC9822219 DOI: 10.3390/molecules28010319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 12/21/2022] [Accepted: 12/25/2022] [Indexed: 01/04/2023]
Abstract
Gastric cancer (GC) is one of the major causes of death worldwide, ranking as the fifth most incident cancer in 2020 and the fourth leading cause of cancer mortality. The majority of GC patients are in an advanced stage at the time of diagnosis, presenting a poor prognosis and outcome. Current GC treatment approaches involve endoscopic detection, gastrectomy and chemotherapy or chemoradiotherapy in an adjuvant or neoadjuvant setting. Drug development approaches demand extreme effort to identify molecular mechanisms of action of new drug candidates. Drug repurposing is based on the research of new therapeutic indications of drugs approved for other pathologies. In this review, we explore GC and the different drugs repurposed for this disease.
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Affiliation(s)
- Diana Araújo
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- Institute of Biomedical Sciences Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
- Institute for Research and Innovation in Health (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho, 45, 4200-135 Porto, Portugal
| | - Eduarda Ribeiro
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- Institute of Biomedical Sciences Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Irina Amorim
- Institute of Biomedical Sciences Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
- Institute for Research and Innovation in Health (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho, 45, 4200-135 Porto, Portugal
| | - Nuno Vale
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- Correspondence: ; Tel.: +351-220426537
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14
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Lan WH, Lin TY, Yeh JA, Feng CL, Hsu JT, Lin HJ, Kuo CJ, Lai CH. Mechanism Underlying Metformin Action and Its Potential to Reduce Gastric Cancer Risk. Int J Mol Sci 2022; 23:14163. [PMID: 36430639 PMCID: PMC9695469 DOI: 10.3390/ijms232214163] [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: 09/29/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/18/2022] Open
Abstract
Diabetes mellitus is associated with a high risk of developing gastric cancer (GC). Metformin, which is conventionally used to treat type 2 diabetes, induces AMP-activated protein kinase signaling and suppresses gluconeogenesis. Recent studies have reported that metformin is associated with beneficial effects in cancer prevention and treatment owing to its anti-tumor effects. This makes metformin a potential medication for GC therapy. However, contradicting reports have emerged regarding the efficacy of metformin in reducing the risk of GC. This review summarizes the impact of metformin on mitigating GC risk by analyzing clinical databases. The mechanism underlying the anti-tumor effect of metformin on GC is also discussed.
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Affiliation(s)
- Wen-Hsi Lan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
| | - Ting-Yu Lin
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
| | - Jia-Ai Yeh
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
| | - Chun-Lung Feng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hsinchu Hospital, Hsinchu 30272, Taiwan
- Department of Internal Medicine, Department of Medical Research, School of Medicine, China Medical University and Hospital, Taichung 40402, Taiwan
| | - Jun-Te Hsu
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
| | - Hwai-Jeng Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang-Ho Hospital, New Taipei 23562, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Chia-Jung Kuo
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
- Chang Gung Microbiota Therapy Center, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
| | - Chih-Ho Lai
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Internal Medicine, Department of Medical Research, School of Medicine, China Medical University and Hospital, Taichung 40402, Taiwan
- Molecular Infectious Disease Research Center, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
- Department of Nursing, Asia University, Taichung 41354, Taiwan
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15
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Witayateeraporn W, Nguyen HM, Ho DV, Nguyen HT, Chanvorachote P, Vinayanuwattikun C, Pongrakhananon V. Aspiletrein A Induces Apoptosis Cell Death via Increasing Reactive Oxygen Species Generation and AMPK Activation in Non-Small-Cell Lung Cancer Cells. Int J Mol Sci 2022; 23:ijms23169258. [PMID: 36012522 PMCID: PMC9409406 DOI: 10.3390/ijms23169258] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/10/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022] Open
Abstract
Lung cancer remains a leading cause of death in cancer patients, and deregulation of apoptosis is a serious concern in clinical practice, even though therapeutic intervention has been greatly improved. Plants are a versatile source of biologically active compounds for anticancer drug discovery, and aspiletrein A (AA) is a steroidal saponin isolated from Aspidistra letreae that has a potent cytotoxic effect on various cancer cell lines. In this study, we investigated and determined the underlying molecular mechanism by which AA induces apoptosis. AA strongly induced apoptosis in NSCLC cells by mediating ROS generation and thereby activating AMP-activated protein kinase (AMPK) signaling. Consequently, downstream signaling and levels of phosphorylated mTOR and Bcl-2 were significantly decreased. Pretreatment with either an antioxidant, N-acetylcysteine, or an AMPK inhibitor, compound C, could reverse the apoptosis-inducing effect and counteract the effect of AA on the AMPK signaling pathway. Decreased levels of Bcl-2 were due to AA-mediating Bcl-2 degradation via a ROS/AMPK/mTOR axis-dependent proteasomal mechanism. Consistently, the apoptotic-inducing effect of AA was also observed in patient-derived malignant lung cancer cells, and it suppressed an in vitro 3D-tumorigenesis. This study identified the underlying mechanism of AA on lung cancer apoptosis, thereby facilitating potential research and development of this compound for further clinical implications.
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Affiliation(s)
- Wasita Witayateeraporn
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Hien Minh Nguyen
- Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam
| | - Duc Viet Ho
- Faculty of Pharmacy, Hue University of Medicine and Pharmacy, Hue City 49000, Vietnam
| | - Hoai Thi Nguyen
- Faculty of Pharmacy, Hue University of Medicine and Pharmacy, Hue City 49000, Vietnam
| | - Pithi Chanvorachote
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Chanida Vinayanuwattikun
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Varisa Pongrakhananon
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Preclinical Toxicity and Efficacy Assessment of Medicines and Chemicals Research Unit, Chulalongkorn University, Bangkok 10330, Thailand
- Correspondence: ; Tel.: +66-2-218-8325; Fax: +66-2-218-8340
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16
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Кузнецов КО, Сафина ЭР, Гаймакова ДВ, Фролова ЯС, Оганесян ИЮ, Садертдинова АГ, Назмиева КА, Исламгулов АХ, Каримова АР, Галимова АМ, Ризванова ЭВ. [Metformin and malignant neoplasms: a possible mechanism of antitumor action and prospects for use in practice]. PROBLEMY ENDOKRINOLOGII 2022; 68:45-55. [PMID: 36337018 PMCID: PMC9762452 DOI: 10.14341/probl13097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 06/16/2023]
Abstract
Metformin is a first-line antidiabetic drug for the treatment of type 2 diabetes mellitus (DM2); its molecular target is AMP-activated protein kinase (AMPK), which is involved in many metabolic processes. Metformin not only reduces blood glucose levels and improves insulin sensitivity, but also inhibits lipolysis and reduces cardiovascular risk in patients with DM2. In recent years, it has been proven that metformin slows down the aging process, stimulates hair growth, eliminates cognitive impairment, and also has an antitumor effect. Most basic studies have shown that metformin inhibits the growth of tumor cells and promotes cellular apoptosis, while clinical studies show contradictory results. This discrepancy can be explained by the difference in the concentration of metformin between basic and clinical studies. The maximum daily dose of metformin for patients with DM2 is 2500 mg / day, and the dose used in basic research was much higher. Metformin directly activates the AMPK signaling pathway, inhibits the production of reactive oxygen species, induces the activation of mTORC1, inhibits cyclin D1, which leads to a reduction in the risk of the occurrence and development of malignant neoplasms. In addition, metformin indirectly inhibits tumor growth, proliferation, invasion and metastasis by reducing the concentration of glucose in the blood, insulin resistance, as well as by reducing inflammation and affecting the tumor microenvironment. Glycolysis plays an important role in the energy metabolism of tumors, and metformin is able to have an inhibitory effect on it. Currently, studies of the mechanism of antitumor effects of metformin are becoming more extensive and in-depth, but there are still some contradictions.
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Affiliation(s)
- К. О. Кузнецов
- Российский национальный исследовательский медицинский университет им. Н.И. Пирогова
| | - Э. Р. Сафина
- Башкирский государственный медицинский университет
| | | | - Я. С. Фролова
- Первый Московский государственный медицинский университет им. И.М. Сеченова
| | - И. Ю. Оганесян
- Первый Московский государственный медицинский университет им. И.М. Сеченова
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17
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Huang F, Xiang Y, Li T, Huang Y, Wang J, Zhang HM, Li HH, Dai ZT, Li JP, Li H, Zhou J, Liao XH. Metformin and MiR-365 synergistically promote the apoptosis of gastric cancer cells via MiR-365-PTEN-AMPK axis. Pathol Res Pract 2022; 230:153740. [PMID: 35007850 DOI: 10.1016/j.prp.2021.153740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 12/10/2021] [Accepted: 12/16/2021] [Indexed: 01/19/2023]
Abstract
Metformin is an oral biguanide used to treat diabetes. Recent study showed it may interfere was related to cancer progression and has a positive effect on cancer prevention and treatment, which attracts a new hot research topic. Here we show that Metformin suppressed the proliferation but induced apoptosis of gastric cells. Notably, Metformin enhanced gastriccell apoptosis via modulating AMPK signaling. Furthermore, Metformin and miR-365 synergistically promote the apoptosis of gastric cancer cells by miR-365-PTEN-AMPK axis. Our study unraveled a novel signaling axis in the regulation in gastric cancer, which could be amplified by the application of metformin. The new effect of metformin potentiates its novel therapeutic application in the future. AVAILABILITY OF DATA AND MATERIALS: The data generated during this study are included in this article and its supplementary information files are available from the corresponding author on reasonable request.
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Affiliation(s)
- Feng Huang
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Yuan Xiang
- Department of Medical Laboratory, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Hubei 430014, PR China.
| | - Ting Li
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - You Huang
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Jun Wang
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Hui-Min Zhang
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Han-Han Li
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Zhou-Tong Dai
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Jia-Peng Li
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Hui Li
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Jun Zhou
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Xing-Hua Liao
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
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18
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Misirkic Marjanovic MS, Vucicevic LM, Despotovic AR, Stamenkovic MM, Janjetovic KD. Dual anticancer role of metformin: an old drug regulating AMPK dependent/independent pathways in metabolic, oncogenic/tumorsuppresing and immunity context. Am J Cancer Res 2021; 11:5625-5643. [PMID: 34873484 PMCID: PMC8640802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 10/29/2021] [Indexed: 06/13/2023] Open
Abstract
Metformin has been known to treat type 2 diabetes for decades and is widely prescribed antidiabetic drug. Recently, its anticancer potential has also been discovered. Moreover, metformin has low cost thus it has attained profound research interest. Comprehensing the complexity of the molecular regulatory networks in cancer provides a mode for advancement of research in cancer development and treatment. Metformin targets many pathways that play an important role in cancer cell survival outcome. Here, we described anticancer activity of metformin on the AMPK dependent/independent mechanisms regulating metabolism, oncogene/tumor suppressor signaling pathways together with the issue of clinical studies. We also provided brief overwiev about recently described metformin's role in cancer immunity. Insight in these complex molecular networks, will simplify application of metformin in clinical trials and contribute to improvement of anti-cancer therapy.
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Affiliation(s)
- Maja S Misirkic Marjanovic
- Department of Neurophysiology, Institute for Biological Research “Sinisa Stankovic”, National Institute of Republic of Serbia, University of BelgradeSerbia
| | - Ljubica M Vucicevic
- Department of Neurophysiology, Institute for Biological Research “Sinisa Stankovic”, National Institute of Republic of Serbia, University of BelgradeSerbia
| | - Ana R Despotovic
- Department of Neurophysiology, Institute for Biological Research “Sinisa Stankovic”, National Institute of Republic of Serbia, University of BelgradeSerbia
| | - Marina M Stamenkovic
- Department of Immunology, Institute of Microbiology and Immunology, Faculty of Medicine, University of BelgradeSerbia
| | - Kristina D Janjetovic
- Department of Neurophysiology, Institute for Biological Research “Sinisa Stankovic”, National Institute of Republic of Serbia, University of BelgradeSerbia
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19
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Fan Y, Ren X, Wang Y, Xu E, Wang S, Ge R, Liu Y. Metformin inhibits the proliferation of canine mammary gland tumor cells through the AMPK/AKT/mTOR signaling pathway in vitro. Oncol Lett 2021; 22:852. [PMID: 34733370 PMCID: PMC8561621 DOI: 10.3892/ol.2021.13113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 06/14/2021] [Indexed: 11/25/2022] Open
Abstract
As an anti-diabetic drug, metformin has been demonstrated to exhibit antitumor effects. However, the mechanisms involved in decreasing tumor formation, including canine mammary gland tumors (CMGTs), are not well elucidated. The aim of the present study was to evaluate the ability of metformin to induce apoptosis and cell cycle arrest in CMGT cells, as well as identifying the pathways underlying these effects. Cell viability was assessed by Cell Counting Kit-8 analysis following treating with metformin. Subsequently, apoptosis and cell cycle progression were assessed by flow cytometry, and the expression of associated proteins was examined. Expression levels of classical AMP-activated protein kinase (AMPK), protein kinase B (AKT), mechanistic target of rapamycin (mTOR) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) were then investigated using western blot analysis. Metformin inhibited the proliferation of CHMm cells in a concentration-dependent manner. Specifically, metformin induced cell cycle arrest in the G0/G1 phases, accompanied by increased expression of p21 and p27, and decreased expression of cyclin D1 and cyclin-dependent kinase 4. Marked levels of apoptosis were observed in CHMm cells alongside the activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase. Also, the level of Bcl-2 was decreased, and that of Bax was increased. The expression of associated signaling molecules revealed that metformin markedly increased the phosphorylation of AMPK in CHMm cells, and decreased the levels of phosphorylated (p-)AKT, p-mTOR and p-4E-BP1, while Compound C reversed these changes. These findings demonstrated that metformin may be a potential therapeutic agent for CMGTs, acting via the AMPK/AKT/mTOR signaling pathway.
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Affiliation(s)
- Yuying Fan
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
| | - Xiaoli Ren
- College of Veterinary Medicine, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan 450046, P.R. China
| | - Yingxue Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
| | - Enshuang Xu
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163000, P.R. China
| | - Shuang Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
| | - Ruidong Ge
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
| | - Yun Liu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
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20
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Tseng HH, Chen YZ, Chou NH, Chen YC, Wu CC, Liu LF, Yang YF, Yeh CY, Kung ML, Tu YT, Tsai KW. Metformin inhibits gastric cancer cell proliferation by regulation of a novel Loc100506691-CHAC1 axis. MOLECULAR THERAPY-ONCOLYTICS 2021; 22:180-194. [PMID: 34514098 PMCID: PMC8416970 DOI: 10.1016/j.omto.2021.08.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 08/13/2021] [Indexed: 12/30/2022]
Abstract
Long noncoding RNAs (lncRNAs) are a group of nonprotein coding transcripts that play a critical role in cancer progression. However, the role of lncRNA in metformin-induced inhibition of cell growth and its biological function in gastric cancer remain largely unknown. In this study, we identified an oncogenic lncRNA, Loc100506691, the expression of which was decreased in gastric cancer cells with metformin treatment. Moreover, Loc100506691 was significantly overexpressed in gastric cancer compared with adjacent normal tissues (p < 0.001), and high Loc100506691 expression was significantly correlated with poor survival of patients with gastric cancer. Additionally, Loc100506691 knockdown could significantly suppress gastric cancer cell growth in vitro, and ectopic Loc100506691 expression accelerated tumor growth in an in vivo mouse model. Analysis of the cell cycle revealed that Loc100506691 knockdown induced cell cycle arrest at the G2/M phase by impairing cell entry from the G2/M to G1 phase. Loc100506691 negatively regulated CHAC1 expression by modulating miR-26a-5p/miR-330-5p expression, and CHAC1 knockdown markedly attenuated Loc100506691 knockdown-induced gastric cancer cell growth and motility suppression. We concluded that anti-proliferative effects of metformin in gastric cancer may be partially caused by suppression of the Loc100506691-miR-26a-5p/miR-330-5p-CHAC1 axis.
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Affiliation(s)
- Hui-Hwa Tseng
- Division of Anatomic Pathology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23124, Taiwan
| | - You-Zuo Chen
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan.,Department of Biological Science and Technology, I-Shou University, Kaohsiung 82445, Taiwan
| | - Nan-Hua Chou
- Department of Surgery Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Yen-Chih Chen
- Division of Gastrointestinal Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical of Foundation, New Taipei City 23124, Taiwan
| | - Chao-Chuan Wu
- Division of Gastrointestinal Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical of Foundation, New Taipei City 23124, Taiwan
| | - Li-Feng Liu
- Department of Biological Science and Technology, I-Shou University, Kaohsiung 82445, Taiwan
| | - Yi-Fang Yang
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Chung-Yu Yeh
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Mei-Lang Kung
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Ya-Ting Tu
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23124, Taiwan
| | - Kuo-Wang Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23124, Taiwan
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21
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Ghouraba MH, Masad RJ, Mpingirika EZ, Abdelraheem OM, Zeghlache R, Alserw AM, Amleh A. Role of NELF-B in supporting epithelial-mesenchymal transition and cell proliferation during hepatocellular carcinoma progression. Oncol Lett 2021; 22:761. [PMID: 34539865 PMCID: PMC8436359 DOI: 10.3892/ol.2021.13022] [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: 01/15/2021] [Accepted: 06/18/2021] [Indexed: 12/24/2022] Open
Abstract
Negative elongation factor-B (NELF-B), also known as cofactor of BRCA1 (COBRA1), is one of the four subunits of the NELF complex. It interacts with BRCA1, in addition to other transcription complexes in various tissues. The NELF complex represses the transcription of several genes by stalling RNA polymerase II during the early phase of transcription elongation. The role of NELF-B in liver cancer and hepatocellular carcinoma (HCC), the most prevalent type of liver cancer, remains to be elucidated. It has been previously demonstrated that silencing of NELF-B inhibits the proliferation and migration of HepG2 cells. The present study aimed to investigate the consequences of ectopic expression and silencing of NELF-B in liver cancer HepG2 and SNU449 cell lines. Functional assays were performed to examine the effects on gene and protein expression, viability, migration and invasion of cells. Overexpression of NELF-B did not alter the proliferation and migration of HepG2 cells, or the expression of tested genes, indicating that overexpression alone may not be sufficient for altering these features in HepG2 cells. By contrast, knockdown of NELF-B in SNU449 cells resulted in decreased cell proliferation, together with induction of apoptosis and decreased expression levels of Ki-67 and survivin, which are markers of proliferation and inhibition of apoptosis, respectively. Additionally, silencing of NELF-B resulted in a significant decrease in the hallmarks of epithelial-mesenchymal transition (EMT), including cell migration and invasion, and decreased the expression levels of EMT markers, such as N-cadherin, vimentin and β-catenin. Decreased expression levels of forkhead box F2 transcription factor and increased mRNA levels of trefoil factor 1, a putative tumor suppressor, were also detected following the silencing of NELF-B. The current results demonstrated that NELF-B enhanced the manifestation of most hallmarks of cancer, including cell proliferation, migration, invasion and inhibition of apoptosis, indicating its critical role in the progression of HCC.
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Affiliation(s)
- Mennatallah Hani Ghouraba
- Department of Biotechnology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Razan Jamil Masad
- Department of Biotechnology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Eric Zadok Mpingirika
- Department of Biotechnology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Omnia Mahmoud Abdelraheem
- Department of Biotechnology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Rached Zeghlache
- Department of Biology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Aya M Alserw
- Department of Biology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Asma Amleh
- Department of Biotechnology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt.,Department of Biology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
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22
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Leng W, Jiang J, Chen B, Wu Q. Metformin and Malignant Tumors: Not Over the Hill. Diabetes Metab Syndr Obes 2021; 14:3673-3689. [PMID: 34429626 PMCID: PMC8380287 DOI: 10.2147/dmso.s326378] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/06/2021] [Indexed: 12/11/2022] Open
Abstract
Malignant tumors are a major cause of death, and their incidence is increasing worldwide. Although the survival rate for some cancers has improved, treatments for other malignant tumors are limited, and their mortality rate continues to increase. People with type 2 diabetes have a higher risk of malignant tumors and a higher mortality rate than those without diabetes. Metformin is a commonly used hypoglycemic drug. In recent years, a growing number of studies have indicated that metformin has antitumor effects and increases the sensitivity of malignant tumors to chemotherapy. However, the effect of metformin on different tumors is currently controversial, and the mechanism of metformin's antitumor action is not fully understood. Insights into the effect of metformin on malignant tumors and the possible mechanism may contribute to the development of antitumor drugs.
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Affiliation(s)
- Weiling Leng
- Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Juan Jiang
- Endocrinology and Nephrology Department, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, People’s Republic of China
| | - Bing Chen
- Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Qinan Wu
- Endocrinology Department, Dazu Hospital of Chongqing Medical University, The People’s Hospital of Dazu, Chongqing, People’s Republic of China
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23
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Tseng CH. The Relationship between Diabetes Mellitus and Gastric Cancer and the Potential Benefits of Metformin: An Extensive Review of the Literature. Biomolecules 2021; 11:1022. [PMID: 34356646 PMCID: PMC8301937 DOI: 10.3390/biom11071022] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/02/2021] [Accepted: 07/08/2021] [Indexed: 12/14/2022] Open
Abstract
The objective of this review is to summarize the findings of published research that investigated the relationship between diabetes mellitus and gastric cancer (GCa) and the potential benefits of metformin on GCa. Related literature has been extensively reviewed, and findings from studies investigating the relationship between diabetes mellitus and GCa suggest that hyperglycemia, hyperinsulinemia and insulin resistance are closely related to the development of GCa. Although not supported by all, most observational studies suggest an increased risk of GCa in patients with type 2 diabetes mellitus, especially in women and in Asian populations. Incidence of second primary malignancy diagnosed after GCa is significantly higher in diabetes patients. Diabetes patients with GCa may have more complications after gastrectomy or chemotherapy and they may have a poorer prognosis than patients with GCa but without diabetes mellitus. However, glycemic control may improve in the diabetes patients with GCa after receiving gastrectomy, especially after procedures that bypass the duodenum and proximal jejunum, such as Roux-en-Y gastric bypass or Billroth II reconstruction. The potential links between diabetes mellitus and GCa may involve the interactions with shared risk factors (e.g., obesity, hyperglycemia, hyperinsulinemia, insulin resistance, high salt intake, smoking, etc.), Helicobacter pylori (HP) infection, medications (e.g., insulin, metformin, statins, aspirin, proton pump inhibitors, antibiotics, etc.) and comorbidities (e.g., hypertension, dyslipidemia, vascular complications, heart failure, renal failure, etc.). With regards to the potential benefits of metformin on GCa, results of most observational studies suggest a reduced risk of GCa associated with metformin use in patients with T2DM, which can be supported by evidence derived from many in vitro and animal studies. Metformin use may also reduce the risk of HP infection, an important risk factor of GCa. In patients with GCa, metformin users may have improved survival and reduced recurrence. More studies are required to clarify the pathological subtypes/anatomical sites of GCa associated with type 2 diabetes mellitus or prevented by metformin, to confirm whether GCa risk can also be increased in patients with type 1 diabetes mellitus and to explore the possible role of gastric microbiota in the development of GCa.
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Affiliation(s)
- Chin-Hsiao Tseng
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 10051, Taiwan; ; Tel.: +886-2-2388-3578
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10051, Taiwan
- Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan 350, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei 100, Taiwan
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24
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Metformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells. Sci Rep 2021; 11:14002. [PMID: 34234193 PMCID: PMC8263563 DOI: 10.1038/s41598-021-93270-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 06/21/2021] [Indexed: 12/16/2022] Open
Abstract
Metformin increased cellular ROS levels in AsPC-1 pancreatic cancer cells, with minimal effect in HDF, human primary dermal fibroblasts. Metformin reduced cellular ATP levels in HDF, but not in AsPC-1 cells. Metformin increased AMPK, p-AMPK (Thr172), FOXO3a, p-FOXO3a (Ser413), and MnSOD levels in HDF, but not in AsPC-1 cells. p-AMPK and p-FOXO3a also translocated from the cytosol to the nucleus by metformin in HDF, but not in AsPC-1 cells. Transfection of si-FOXO3a in HDF increased ROS levels, while wt-FOXO3a-transfected AsPC-1 cells decreased ROS levels. Metformin combined with apigenin increased ROS levels dramatically and decreased cell viability in various cancer cells including AsPC-1 cells, with each drug used singly having a minimal effect. Metformin/apigenin combination synergistically decreased mitochondrial membrane potential in AsPC-1 cells but to a lesser extent in HDF cells. Metformin/apigenin combination in AsPC-1 cells increased DNA damage-, apoptosis-, autophagy- and necroptosis-related factors, but not in HDF cells. Oral administration with metformin/apigenin caused dramatic blocks tumor size in AsPC-1-xenografted nude mice. Our results suggest that metformin in cancer cells differentially regulates cellular ROS levels via AMPK-FOXO3a-MnSOD pathway and combination of metformin/apigenin exerts anticancer activity through DNA damage-induced apoptosis, autophagy and necroptosis by cancer cell-specific ROS amplification.
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25
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Cheung KS, Chung KL, Leung WK. Chemopreventive Effect of Metformin on Gastric Cancer Development. Gut Liver 2021; 16:147-156. [PMID: 34158423 PMCID: PMC8924804 DOI: 10.5009/gnl210132] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/17/2021] [Accepted: 05/12/2021] [Indexed: 12/24/2022] Open
Abstract
Although Helicobacterpylori infection is the most important causative factor for gastric cancer (GC), H. pylori eradication alone does not completely eliminate the GC risk. In addition to H. pylori eradication, other risk factors for GC should be identified and targeted. Diabetes mellitus (DM) confers a 20% increased risk of GC, which could be mediated via several biological mechanisms including the stimulation of cell proliferation via hyperinsulinemia and increased insulin-growth factor production, the promotion of angiogenesis, and DNA damage. With a current global prevalence of 9.3% and a predicted rise to 10.2% by 2030, DM could contribute substantially to the burden of GC cases worldwide. Emerging evidence showed that metformin possesses chemopreventive effects via both direct (e.g., adenosine monophosphate-activated protein kinase activation and subsequent inhibition of the mammalian target of rapamycin pathway) and indirect (e.g., modulation of the interaction between tumor cells and their microenvironment and gut microbiota) pathways. A recent meta-analysis of observational studies showed that metformin use was associated with 24% lower GC risk. However, many available observational studies related to metformin effects suffered from biases including the failure to adjust for the H. pylori infection status and serial glycemic control and time-related biases. Future prospective studies addressing these pitfalls are needed.
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Affiliation(s)
- Ka Shing Cheung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.,Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Kit Lam Chung
- Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wai K Leung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
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26
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Anticancer potential of metformin: focusing on gastrointestinal cancers. Cancer Chemother Pharmacol 2021; 87:587-598. [PMID: 33744985 DOI: 10.1007/s00280-021-04256-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 03/08/2021] [Indexed: 12/15/2022]
Abstract
Gastrointestinal cancers are one of the most common types of cancer that have high annual mortality; therefore, identification and introduction of safe drugs in the control and prevention of these cancers are of particular importance. Metformin, a lipophilic biguanide, is the most commonly prescribed agent for type 2 diabetes management. In addition to its great effects on lowering the blood glucose concentrations, the anti-cancer properties of this drug have been reported in many types of cancers such as gastrointestinal cancers. Hence the effects of this agent as a safe drug on the reduction of gastrointestinal cancer risk and suppression of these types of cancers have been studied in different clinical trials. Furthermore, the proposed mechanisms of metformin in preventing the growth of these cancers have been investigated in several studies. In this review, we discuss recent advances in elucidating the molecular mechanisms that are relevant for metformin use in gastrointestinal cancer treatment.
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27
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Giaccari A, Solini A, Frontoni S, Del Prato S. Metformin Benefits: Another Example for Alternative Energy Substrate Mechanism? Diabetes Care 2021; 44:647-654. [PMID: 33608326 PMCID: PMC7896249 DOI: 10.2337/dc20-1964] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 12/03/2020] [Indexed: 02/03/2023]
Abstract
Since the UK Prospective Diabetes Study (UKPDS), metformin has been considered the first-line medication for patients with newly diagnosed type 2 diabetes. Though direct evidence from specific trials is still lacking, several studies have suggested that metformin may protect from diabetes- and nondiabetes-related comorbidities, including cardiovascular, renal, neurological, and neoplastic diseases. In the past few decades, several mechanisms of action have been proposed to explain metformin's protective effects, none being final. It is certain, however, that metformin increases lactate production, concentration, and, possibly, oxidation. Once considered a mere waste product of exercising skeletal muscle or anaerobiosis, lactate is now known to act as a major energy shuttle, redistributed from production sites to where it is needed. Through the direct uptake and oxidation of lactate produced elsewhere, all end organs can be rapidly supplied with fundamental energy, skipping glycolysis and its possible byproducts. Increased lactate production (and consequent oxidation) could therefore be considered a positive mechanism of action of metformin, except when, under specific circumstances, metformin and lactate become excessive, increasing the risk of lactic acidosis. We are proposing that, rather than considering metformin-induced lactate production as dangerous, it could be considered a mechanism through which metformin exerts its possible protective effect on the heart, kidneys, and brain and, to some extent, its antineoplastic action.
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Affiliation(s)
- Andrea Giaccari
- Center for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Anna Solini
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy
| | - Simona Frontoni
- Unit of Endocrinology, Diabetes and Metabolism, San Giovanni Calibita Fatebenefratelli Hospital, Rome, Italy
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Stefano Del Prato
- Section of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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28
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Drzewoski J, Hanefeld M. The Current and Potential Therapeutic Use of Metformin-The Good Old Drug. Pharmaceuticals (Basel) 2021; 14:122. [PMID: 33562458 PMCID: PMC7915435 DOI: 10.3390/ph14020122] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023] Open
Abstract
Metformin, one of the oldest oral antidiabetic agents and still recommended by almost all current guidelines as the first-line treatment for type 2 diabetes mellitus (T2DM), has become the medication with steadily increasing potential therapeutic indications. A broad spectrum of experimental and clinical studies showed that metformin has a pleiotropic activity and favorable effect in different pathological conditions, including prediabetes, type 1 diabetes mellitus (T1DM) and gestational diabetes mellitus (GDM). Moreover, there are numerous studies, meta-analyses and population studies indicating that metformin is safe and well tolerated and may be associated with cardioprotective and nephroprotective effect. Recently, it has also been reported in some studies, but not all, that metformin, besides improvement of glucose homeostasis, may possibly reduce the risk of cancer development, inhibit the incidence of neurodegenerative disease and prolong the lifespan. This paper presents some arguments supporting the initiation of metformin in patients with newly diagnosed T2DM, especially those without cardiovascular risk factors or without established cardiovascular disease or advanced kidney insufficiency at the time of new guidelines favoring new drugs with pleotropic effects complimentary to glucose control. Moreover, it focuses on the potential beneficial effects of metformin in patients with T2DM and coexisting chronic diseases.
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Affiliation(s)
- Józef Drzewoski
- Central Teaching Hospital of Medical University of Lodz, 92-213 Lodz, Poland
| | - Markolf Hanefeld
- Medical Clinic III, Department of Medicine Technical University Dresden, 01307 Dresden, Germany;
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29
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Chen J, Huang Y, Tang Z, Li M, Ling X, Liao J, Zhou X, Fang S, Zhao H, Zhong W, Yuan X. Genome-Scale CRISPR-Cas9 Transcriptional Activation Screening in Metformin Resistance Related Gene of Prostate Cancer. Front Cell Dev Biol 2021; 8:616332. [PMID: 33575255 PMCID: PMC7870801 DOI: 10.3389/fcell.2020.616332] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/09/2020] [Indexed: 01/01/2023] Open
Abstract
Metformin is a classic type II diabetes drug which possesses anti-tumor properties for various cancers. However, different cancers do not respond to metformin with the same effectiveness or acquire resistance. Thus, searching for vulnerabilities of metformin-resistant prostate cancer is a promising strategy to improve the therapeutic efficiency of the drug. A genome-scale CRISPR-Cas9 activation library search targeting 23,430 genes was conducted to identify the genes that confer resistance to metformin in prostate cancer cells. Candidate genes were selected by total reads of sgRNA and sgRNA diversity, and then a CCK8 assay was used to verify their resistance to metformin. Interestingly, we discovered that the activation of ECE1, ABCA12, BPY2, EEF1A1, RAD9A, and NIPSNAP1 contributed to in vitro resistance to metformin in DU145 and PC3 cell lines. Notably, a high level of RAD9A, with poor prognosis in PCa, was the most significant gene in the CCK8 assay. Furthermore, we discerned the tumor immune microenvironment with RAD9A expression by CIBERSORT. These results suggested that a high level of RAD9A may upregulate regulatory T cells to counterbalance metformin in the tumor immune microenvironment.
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Affiliation(s)
- Jiahong Chen
- Department of Urology, Huizhou Municipal Central Hospital, Huizhou, China
| | - Yaqiang Huang
- Department of Urology, Zhongshan City People's Hospital, Zhongshan, China
| | - Zhenfeng Tang
- Guangdong Key Laboratory of Urology, Department of Urology, Minimally Invasive Surgery Center, Guangzhou Urology Research Institute, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Maozhang Li
- Department of Urology, Huizhou Municipal Central Hospital, Huizhou, China
| | - Xiaohui Ling
- Reproductive Medicine Centre, Huizhou Central People's Hospital, Guangdong Medical University, Huizhou, China
| | - Jinxian Liao
- Department of Urology, Huizhou Municipal Central Hospital, Huizhou, China
| | - Xiaobo Zhou
- Department of Urology, Huizhou Municipal Central Hospital, Huizhou, China
| | - Shumin Fang
- Department of Urology, Huizhou Municipal Central Hospital, Huizhou, China
| | - Haibo Zhao
- Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Weide Zhong
- Department of Urology, Huizhou Municipal Central Hospital, Huizhou, China.,Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Department of Urology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Xia Yuan
- Department of Urology, Huizhou Municipal Central Hospital, Huizhou, China
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30
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Lou S, Zhang J, Zhai Z, Yin X, Wang Y, Fang T, Xue Y. The landscape of alternative splicing reveals novel events associated with tumorigenesis and the immune microenvironment in gastric cancer. Aging (Albany NY) 2021; 13:4317-4334. [PMID: 33428603 PMCID: PMC7906195 DOI: 10.18632/aging.202393] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 10/22/2020] [Indexed: 12/24/2022]
Abstract
Alternative splicing (AS), contributing to vast protein diversity from a rather limited number of genes in eukaryotic transcripts, has emerged as an important signature for tumor initiation and progression. However, a systematic understanding of its functional impact and relevance to gastric cancer (GC) tumorigenesis is lacking. Differentially expressed AS (DEAS) was verified among GC-associated AS events based on RNA-seq profiles from the TCGA database. Functional enrichment analysis, unsupervised clustering analysis and prognostic models were used to infer the potential roles of DEAS events and their molecular, clinical and immune features. In total, 12,225 AS events were detected from 5,199 genes, among which 314 AS events were identified as DEAS events in GC. The parental genes of the DEAS events were significantly enriched in the regulation of GC-related processes. The splicing correlation network suggested a significant relationship between DEAS events and splicing factors (SFs). Three clusters of DEAS events were identified to be different in prognosis, cancer-specific signatures and immune features between distinct clusters. Univariate and multivariate analyses regarded 3 DEAS events as independent prognostic indicators. Profiling of the AS landscape in GC elucidated the functional roles of the splicing network in GC and might serve as a novel prognostic indicator and therapeutic target.
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Affiliation(s)
- Shenghan Lou
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, 150081 Harbin, Heilongjiang Province, China
| | - Jian Zhang
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, 150081 Harbin, Heilongjiang Province, China
| | - Zhao Zhai
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, 150081 Harbin, Heilongjiang Province, China
| | - Xin Yin
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, 150081 Harbin, Heilongjiang Province, China
| | - Yimin Wang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, 150081 Harbin, Heilongjiang Province, China
| | - Tianyi Fang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, 150081 Harbin, Heilongjiang Province, China
| | - Yingwei Xue
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, 150081 Harbin, Heilongjiang Province, China
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31
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Jiang S, Lu Q. A new contribution for an old drug: Prospect of metformin in colorectal oncotherapy. J Cancer Res Ther 2021; 17:1608-1617. [PMID: 35381729 DOI: 10.4103/jcrt.jcrt_1824_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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32
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Zhang J, Wen L, Zhou Q, He K, Teng L. Preventative and Therapeutic Effects of Metformin in Gastric Cancer: A New Contribution of an Old Friend. Cancer Manag Res 2020; 12:8545-8554. [PMID: 32982447 PMCID: PMC7505710 DOI: 10.2147/cmar.s264032] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/19/2020] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer (GC) is a cancer with high prevalence, and is one of the leading causes of cancer death worldwide. Metformin is a widely used hypoglycemic agent for type-2 diabetes mellitus (T2DM). Recently, metformin has drawn increasing attention in the field of cancer research for its emerging anti-cancer roles. However, the efficacy and underlying molecular mechanisms of metformin in the prevention and treatment for GC remain controversial. This review summarized the present clinical and mechanistic studies that investigated the efficacy of metformin in GC. It was found that the majority of clinical studies affirmed protective roles of metformin in both gastric cancer risk and survival rate. In addition, metformin’s effects in the prevention and treatment for GC involve multiple pathways mainly via AMPK and IGF-1R. It was concluded that metformin presents a unique opportunity for application against GC, but further clinical and mechanistic investigations are required to solidify the roles of metformin in GC.
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Affiliation(s)
- Jing Zhang
- Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Liping Wen
- Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Quan Zhou
- Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Kuifeng He
- Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lisong Teng
- Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
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Cho MH, Yoo TG, Jeong SM, Shin DW. Association of Aspirin, Metformin, and Statin Use with Gastric Cancer Incidence and Mortality: A Nationwide Cohort Study. Cancer Prev Res (Phila) 2020; 14:95-104. [PMID: 32938643 DOI: 10.1158/1940-6207.capr-20-0123] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 07/06/2020] [Accepted: 09/04/2020] [Indexed: 12/24/2022]
Abstract
Anticancer effects of aspirin, metformin, and statins against gastric cancer, one of the most common cancers in the world, have been reported. This retrospective cohort study aimed to investigate independent associations of aspirin, metformin, and statin use with gastric cancer incidence and mortality after adjustment for concomitant use of other drugs, using pooled cohort data extracted from the Korean National Health Insurance claim database. Follow-up started on January 1, 2004 and ended at the date of gastric cancer diagnosis, death, or December 31, 2013. Exposures to drugs were defined as cumulative duration of use for aspirin and cumulative defined daily dose for metformin and statin, and were entered as time-dependent variables in Cox analysis models to avoid immortal time bias. Use of aspirin for longer than 182.5 and 547.5 days during 2-year interval was associated with reduced risks of gastric cancer incidence and mortality, respectively. Patients with diabetes were at higher risk of gastric cancer incidence and mortality than nondiabetic people, regardless of metformin treatment. However, metformin use among patients with diabetes was associated with a reduction in gastric cancer mortality in a dose-response manner. Statin use was also associated with a reduction of gastric cancer mortality in the general population, but not with gastric cancer incidence. In conclusion, long-term use of aspirin was independently associated with reduced incidence and mortality of gastric cancer in the general population, but metformin or statin use was only associated with a reduction of gastric cancer mortality in patients with diabetes and in the general population, respectively. PREVENTION RELEVANCE: Long-term use of aspirin was independently associated with reduced incidence and mortality of gastric cancer in the general population. Metformin or statin use, however, was only associated with a reduction of gastric cancer mortality in diabetic patients and in the general population in a dose-response manner, respectively.
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Affiliation(s)
- Mi Hee Cho
- Samsung C&T Medical Clinic, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Jongno-gu, Seoul, Republic of Korea (South)
| | - Tae Gon Yoo
- Department of Family Medicine, Hongseong Medical Center, Hongseong-gun, Chungcheongnam-do, Republic of Korea (South)
| | - Su-Min Jeong
- Department of Family Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Gwanak-gu, Seoul, Republic of Korea (South)
- Department of Family Medicine, Seoul National University Health Service Center, Gwanak-gu, Seoul, Republic of Korea (South)
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Family Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Jongno-gu, Seoul, Republic of Korea (South)
| | - Dong Wook Shin
- Department of Family Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Jongno-gu, Seoul, Republic of Korea (South).
- Supportive Care Center, Samsung Comprehensive Cancer Center, Gangnam-gu, Seoul, Republic of Korea (South)
- Department of Digital Health, SAIHST, Sungkyunkwan University, Jongno-gu, Seoul, Republic of Korea (South)
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Cai L, Jin X, Zhang J, Li L, Zhao J. Metformin suppresses Nrf2-mediated chemoresistance in hepatocellular carcinoma cells by increasing glycolysis. Aging (Albany NY) 2020; 12:17582-17600. [PMID: 32927432 PMCID: PMC7521529 DOI: 10.18632/aging.103777] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 06/29/2020] [Indexed: 01/24/2023]
Abstract
The diabetes drug metformin has recently been shown to possess anti-cancer properties when used with other chemotherapeutic drugs. However, detailed mechanisms by which metformin improves cancer treatment are poorly understood. Here we provide evidence in HepG2 hepatocellular carcinoma cells that metformin sensitizes cisplatin-resistant HepG2 cells (HepG2/DDP) through increasing cellular glycolysis and suppressing Nrf2-dependent transcription. We show that metformin increases glucose uptake and enhances glucose metabolism through glycolytic pathway, resulting in elevated concentrations of intracellular NADPH and lactate. Consistently, high glucose medium suppresses Nrf2-dependent transcription and sensitizes HepG2/DDP cells to cisplatin. Elevated glycolysis was required for metformin to regulate Nrf2-dependent transcription and cisplatin sensitivity, as inhibition of glycolysis with 2-Deoxy-D-glucose (2-DG) significantly mitigates the beneficial effect of metformin. Together, our study has revealed an important biological process and gene transcriptional program underlying the beneficial effect of metformin on reducing chemo-resistance in HepG2 cells and provided new information on improving chemotherapy of liver cancers.
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Affiliation(s)
- Liangyu Cai
- Department of Hepatobiliary and Pancreatic Surgery, Key Laboratory of Nanobiological Technology of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Xin Jin
- Department of Hepatobiliary and Pancreatic Surgery, Key Laboratory of Nanobiological Technology of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Jiannan Zhang
- Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi 214071, Jiangsu, China
| | - Le Li
- Hunan Yuantai Biotechnology Co., Ltd, Changsha 410000, Hunan, China
| | - Jinfeng Zhao
- Department of Hepatobiliary and Pancreatic Surgery, Key Laboratory of Nanobiological Technology of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
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Hu JW, Chen B, Zhang J, Qi YP, Liang JH, Zhong JH, Xiang BD. Novel combination of celecoxib and metformin improves the antitumor effect by inhibiting the growth of Hepatocellular Carcinoma. J Cancer 2020; 11:6437-6444. [PMID: 33033527 PMCID: PMC7532521 DOI: 10.7150/jca.47532] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 08/27/2020] [Indexed: 01/27/2023] Open
Abstract
Objective: To explore the effect of COX-2 inhibitor celecoxib in combination with metformin on the prevention of Hepatocellular carcinoma (HCC) and the mechanisms involved. Methods: HCC cell lines and an HCC rat model were treated with celecoxib, metformin or a combination of both. Cell viability and tumor formation were measured. Results: In vitro and in vivo studies showed that treatment with a combination of celecoxib and metformin inhibited proliferation of HCC to a greater extent than either treatment alone, by reducing the phosphorylation of MTOR. Conclusion: The study suggested that celecoxib combined with metformin would be more effective for the preventing occurrence of HCC than either treatment alone and this combination of therapy is worthy of further study.
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Affiliation(s)
| | | | | | | | | | - Jian-Hong Zhong
- Hepatobiliary Surgery Department, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Key Laboratory for High-Incidence Tumor Prevention and Treatment, Ministry of Education, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Bang-De Xiang
- Hepatobiliary Surgery Department, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Key Laboratory for High-Incidence Tumor Prevention and Treatment, Ministry of Education, Guangxi Medical University Cancer Hospital, Nanning, China
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Kirtonia A, Gala K, Fernandes SG, Pandya G, Pandey AK, Sethi G, Khattar E, Garg M. Repurposing of drugs: An attractive pharmacological strategy for cancer therapeutics. Semin Cancer Biol 2020; 68:258-278. [PMID: 32380233 DOI: 10.1016/j.semcancer.2020.04.006] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/20/2020] [Accepted: 04/22/2020] [Indexed: 02/07/2023]
Abstract
Human malignancies are one of the major health-related issues though out the world and anticipated to rise in the future. The development of novel drugs/agents requires a huge amount of cost and time that represents a major challenge for drug discovery. In the last three decades, the number of FDA approved drugs has dropped down and this led to increasing interest in drug reposition or repurposing. The present review focuses on recent concepts and therapeutic opportunities for the utilization of antidiabetics, antibiotics, antifungal, anti-inflammatory, antipsychotic, PDE inhibitors and estrogen receptor antagonist, Antabuse, antiparasitic and cardiovascular agents/drugs as an alternative approach against human malignancies. The repurposing of approved non-cancerous drugs is an effective strategy to develop new therapeutic options for the treatment of cancer patients at an affordable cost in clinics. In the current scenario, most of the countries throughout the globe are unable to meet the medical needs of cancer patients because of the high cost of the available cancerous drugs. Some of these drugs displayed potential anti-cancer activity in preclinic and clinical studies by regulating several key molecular mechanisms and oncogenic pathways in human malignancies. The emerging pieces of evidence indicate that repurposing of drugs is crucial to the faster and cheaper discovery of anti-cancerous drugs.
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Affiliation(s)
- Anuradha Kirtonia
- Amity Institute of Molecular Medicine and Stem cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida, 201313, India; Equal contribution
| | - Kavita Gala
- Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be University), Vile Parle West, Mumbai, 400056, India; Equal contribution
| | - Stina George Fernandes
- Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be University), Vile Parle West, Mumbai, 400056, India; Equal contribution
| | - Gouri Pandya
- Amity Institute of Molecular Medicine and Stem cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida, 201313, India; Equal contribution
| | - Amit Kumar Pandey
- Amity Institute of Biotechnology, Amity University Haryana, Manesar, Haryana, 122413, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Ekta Khattar
- Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be University), Vile Parle West, Mumbai, 400056, India.
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida, 201313, India.
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Terasaki F, Sugiura T, Okamura Y, Ito T, Yamamoto Y, Ashida R, Ohgi K, Uesaka K. Oncological benefit of metformin in patients with pancreatic ductal adenocarcinoma and comorbid diabetes mellitus. Langenbecks Arch Surg 2020; 405:313-324. [PMID: 32367394 DOI: 10.1007/s00423-020-01874-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 03/29/2020] [Indexed: 12/14/2022]
Abstract
PURPOSE Some clinical studies have suggested that metformin improved prognoses in several cancers. This study aimed to identify prognostic factors for pancreatic ductal adenocarcinoma (PDAC) and determine the utility of metformin administration. METHODS Between January 2007 and December 2015, 373 consecutive patients underwent curative surgery for PDAC. Among the patients, 121 were diagnosed as having diabetes mellitus (DM) before surgery. The characteristics and overall survival (OS) between patients with and without DM were compared retrospectively. Based on their metformin intake, patients with DM were divided into two groups. OS rates between patients with and without metformin intake were compared. Univariate and multivariate analyses were performed to identify prognostic factors for OS among all patients and those with PDAC and DM. RESULTS No significant differences in the 5-year survival rates between patients with and without DM were observed. Among the 121 patients with DM, 18 received metformin and 103 did not (other medications group). The 5-year survival rate was significantly better in the metformin group than in the other medications group (66.7% and 24.4%, respectively; p = 0.034). Multivariate analysis identified pN1 (p = 0.002), metformin administration (p = 0.022), and microvascular invasion (p = 0.023) as independent prognostic factors for OS in the patients with DM. Matched-pair analysis showed that OS tended to be better in the metformin group than in the other medications group (p = 0.067). CONCLUSIONS History of metformin intake may contribute to favorable prognosis in patients with PDAC and pre-existing DM.
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Affiliation(s)
- Fumihiro Terasaki
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Teiichi Sugiura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.
| | - Yukiyasu Okamura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Takaaki Ito
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Yusuke Yamamoto
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Ryo Ashida
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Katsuhisa Ohgi
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Katsuhiko Uesaka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
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Shao X, Cheng Z, Xu M, Mao J, Wang J, Zhou C. Prognosis, Significance and Positive Correlation of Rab1A and p-S6K/Gli1 Expression in Gastric Cancer. Anticancer Agents Med Chem 2020; 19:1359-1367. [PMID: 31038077 DOI: 10.2174/1871520619666190416110851] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 10/23/2018] [Accepted: 04/03/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND Gastric Cancer (GC) is a frequently common malignancy. Recent studies have reported Rab1A as an activator of mTORC1, and the mTOR1 pathway is involved in regulating Gli1 expression in several cancers. Only a few studies have been performed to explore the relationship between Rab1A and p-S6K/Gli1in GC. METHODS Immunohistochemistry (IHC) was performed to explore the association of Rab1A/p-S6K/Gli1 expression and prognosis in 117 GC tissue samples and adjacent normal tissues. RESULTS Our results indicated that Rab1A/p-S6K/Gli1 was significantly overexpressed in GC tissues. High expression of Rab1A was closely related to the tumor size and the depth of tumor invasion. In addition, Rab1A expression was closely related with p-S6K/Gli1 expression in GC, and high level of Rab1A/p-S6K/Gli1 caused worse prognosis of GC patients. The univariate and multivariate analysis indicated that the expression of Rab1A was an independent prognostic factor. Moreover, both high Rab1A and p-S6K expression led to a worse prognosis when compared to a single positive expression as well as both high Rab1A/Gli1 expression also led to a worse prognosis than the single positive expression of Rab1A/Gli1. Strikingly, the overexpression of p-S6K also led to a worse prognosis in Rab1A positive patients, as did Gli1. CONCLUSION Our results indicate that Rab1A/mTOR/S6K/Gli1 axis played a crucial role in GC, which may provide a novel field on targeted therapy of GC, especially for mTORC1-targeted therapy-resistant cancers.
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Affiliation(s)
- Xinyu Shao
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215006, China
| | - Zhengwu Cheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, China
| | - Menglin Xu
- Department of Oncology, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, China
| | - Jiading Mao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, China
| | - Junfeng Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, China
| | - Chunli Zhou
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215006, China
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Wang J, Li Y, Ma Q, Huang J. miR‑378 in combination with ultrasonic irradiation and SonoVue microbubbles transfection inhibits hepatoma cell growth. Mol Med Rep 2020; 21:2493-2501. [PMID: 32236628 PMCID: PMC7185276 DOI: 10.3892/mmr.2020.11045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 02/20/2020] [Indexed: 12/16/2022] Open
Abstract
Ultrasonic microbubbles in combination with microRNA (miRNAs/miRs) exhibited promising effects on cancer treatments. The aim was to investigate the role of miR-378 in hepatoma cells and the efficiency of it in combination with ultrasonic irradiation and SonoVue® microbubbles method for cell transfection. HuH-7, Hep3B and SK-Hep1 cells were transfected with an miR-378 mimic using only Lipofectamine® 3000 or combined with SonoVue microbubbles and ultrasonic irradiation at 0.5 W/cm2 for 30 sec. mRNAs and protein levels of Cyclin D1, Bcl-2, Bax, Akt, p53 and Survivin were detected by reverse transcription-quantitative PCR and western blotting, respectively. Cell survival rate, proliferation, cell cycle and apoptosis were determined by Cell Counting Kit-8, cell double cytochemical staining and flow cytometry, respectively. It was found that using a combination of ultrasonic irradiation and the SonoVue microbubbles method increased the effectiveness of miR-378 transfection into hepatocellular carcinoma (HCC) cells, and increased the inhibition of cell survival and proliferation. Moreover, miR-378 increased the rate of apoptosis and upregulated the expression of Bax and p53, and suppressed the cell cycle and downregulated the expression of Cyclin D1, Bcl-2, Akt, β-catenin and Survivin much more effectively in the HCC cell line by applying the combined method. Thus, miR-378 was shown to be a suppressive factor to reduce proliferation and increase apoptosis in HCC cells. Additionally, the combination of ultrasonic irradiation and SonoVue microbubbles method was more efficient in the transfection of miRNA.
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Affiliation(s)
- Jianjun Wang
- Department of Ultrasonography, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Yunchun Li
- Laboratory Center, Jinshan Hospital of Fudan University, Shanghai 201508, P.R. China
| | - Qianfeng Ma
- Department of Ultrasonography, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Jiaxin Huang
- Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, SAR, P.R. China
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Naffaa ME, Rosenberg V, Watad A, Tiosano S, Yavne Y, Chodick G, Amital H, Shalev V. Adherence to metformin and the onset of rheumatoid arthritis: a population-based cohort study. Scand J Rheumatol 2020; 49:173-180. [PMID: 32208872 DOI: 10.1080/03009742.2019.1695928] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Objective: The aim of this retrospective cohort study was to examine whether adherence to metformin treatment may be associated with lower onset of rheumatoid arthritis (RA).Method: Using the computerized databases of a 2.3-million state-mandated health services organization in Israel, we identified incident RA cases among a cohort of 113 749 adult patients who initiated metformin therapy between 1998 and 2014. Adherence was assessed by calculating the mean proportion of follow-up days covered (PDC) with metformin.Results: During the 18 year study period, there were 558 incident RA cases (61 per 100 000 person-years). Adherence to metformin treatment was associated with a lower risk of developing RA, with the lowest risk recorded among patients with a PDC of 40-59% [adjusted hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.45-0.84] compared with non-adherent patients (PDC < 20%). A mean daily metformin dose of 2550 mg or more was also associated with a lower risk of developing RA (adjusted HR 0.62, 95% CI 0.46-0.84) compared to a daily dose of 850 mg or less. In stratified analyses by gender, the negative association between adherence and the risk of RA was limited to women alone.Conclusions: Adherence to metformin treatment is associated with a reduced risk of developing RA in women. Further studies are needed to assess the effect of metformin on RA development in other patient populations.
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Affiliation(s)
- M E Naffaa
- Rheumatology Unit, Galilee Medical Center, Nahariya, Israel
| | - V Rosenberg
- Epidemiology and Database Research, Maccabi Healthcare Services, Tel Aviv, Israel
| | - A Watad
- Department of Medicine 'B', The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - S Tiosano
- Department of Medicine 'B', The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Y Yavne
- Department of Medicine 'B', The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - G Chodick
- Epidemiology and Database Research, Maccabi Healthcare Services, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - H Amital
- Department of Medicine 'B', The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - V Shalev
- Epidemiology and Database Research, Maccabi Healthcare Services, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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The effect of metformin on gastric cancer in patients with type 2 diabetes: a systematic review and meta-analysis. Clin Transl Oncol 2020; 22:1580-1590. [PMID: 32060719 DOI: 10.1007/s12094-020-02304-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 01/18/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Metformin, a drug widely used in the treatment of diabetes, has proven preventive and survival benefits for various malignancies. However, the effect of metformin on gastric cancer risk and survival rate in T2DM patients remains controversial. Therefore, we conducted a systematic review and meta-analysis to evaluate the effect of metformin on gastric cancer in T2DM patients. METHODS We searched PubMed, EMBASE, Medline and the Cochrane Library for related studies up to October 22, 2019. Pooled hazard ratios with 95% confidence intervals were calculated using random-effects model. Heterogeneity was assessed. All articles were evaluated by Newcastle-Ottawa Scale. RESULTS A total of 11 cohort studies met eligibility criteria and were included in the meta-analysis. The use of metformin was related to a significant 21% reduction in GC incidence (HR 0.790; 95% CI 0.624-1.001). Subgroup analysis showed that the use of metformin significantly reduced the risk of gastric cancer in T2DM patients in Asian populations, but not in western populations. In a pooled analysis of 3 studies, metformin use was associated with increased overall survival rate (HR 0.817; 95% CI 0.600-1.113) and cancer-specific survival rate (HR 0.824; 95% CI 0.614-1.106) of T2DM patients. CONCLUSIONS Metformin could reduce the risk of gastric cancer in T2DM patients, particularly in Asian populations. However, it is debatable whether metformin use can improve the prognosis of gastric cancer in T2DM patients.
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Sun X, Zhang X, Zhai H, Zhang D, Ma S. Chicoric acid (CA) induces autophagy in gastric cancer through promoting endoplasmic reticulum (ER) stress regulated by AMPK. Biomed Pharmacother 2019; 118:109144. [PMID: 31545234 DOI: 10.1016/j.biopha.2019.109144] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 06/15/2019] [Accepted: 06/15/2019] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer is one of the most common cancers leading to tumor-related deaths worldwide. Chicoric acid (CA) exhibits a variety of protective effects in different diseases. However, its role in regulating tumor progression has not been reported. Autophagy, as a conserved catabolic process, sustains cellular homoeostasis responding to stress to modulate cell fate. In the study, the effects of CA on gastric cancer were investigated. The results indicated that CA treatment markedly reduced the cell viability and induced apoptosis in gastric cancer cells, and prevented tumor growth in an established xenograft gastric cancer model. Furthermore, CA exposure significantly induced autophagy both in gastric cancer cells and tumor samples, as evidenced by the up-regulated expression of LC3II. Moreover, phosphorylated AMP-activated protein kinase (AMPK) and p70S6 kinase (p70s6k) expression were obviously promoted by CA in vitro and in vivo. Importantly, blocking AMPK activation abrogated CA-induced expression of LC3II in gastric cancer cells. In addition, endoplasmic reticulum (ER) stress in tumor samples or cells was markedly induced by CA treatment through promoting the expression of associated signals such as Parkin, protein kinase RNA-like ER kinase (PERK), activating transcription factors 4 (ATF4) and ATF6. Importantly, these effects were abolished by the inhibition of AMPK signaling. Collectively, our findings indicated that CA prevents human gastric cancer progression by inducing autophagy partly through the activation of AMPK, and represents an effective therapeutic strategy against gastric cancer development.
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Affiliation(s)
- Xiaoli Sun
- Department of General Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Xinwu Zhang
- Department of General Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Hongjun Zhai
- Department of General Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.
| | - Di Zhang
- Department of General Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Shuangyu Ma
- Department of General Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
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Wang H, Luo YH, Shen GN, Piao XJ, Xu WT, Zhang Y, Wang JR, Feng YC, Li JQ, Zhang Y, Zhang T, Wang SN, Xue H, Wang HX, Wang CY, Jin CH. Two novel 1,4‑naphthoquinone derivatives induce human gastric cancer cell apoptosis and cell cycle arrest by regulating reactive oxygen species‑mediated MAPK/Akt/STAT3 signaling pathways. Mol Med Rep 2019; 20:2571-2582. [PMID: 31322207 PMCID: PMC6691246 DOI: 10.3892/mmr.2019.10500] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 04/12/2019] [Indexed: 12/15/2022] Open
Abstract
1,4-Naphthoquinone derivatives have superior anticancer effects, but their use has been severely limited in clinical practice due to adverse side effects. To reduce the side effects and extend the anticancer effects of 1,4-naphthoquinone derivatives, 2-(butane-1-sulfinyl)-1,4-naphthoquinone (BQ) and 2-(octane-1-sulfinyl)-1,4-naphthoquinone (OQ) were synthesized, and their anticancer activities were investigated. The anti-proliferation effects, determined by MTT assays, showed that BQ and OQ significantly inhibited the viability of gastric cancer cells and had no significant cytotoxic effect on normal cell lines. The apoptotic effect was determined by flow cytometry, and the results showed that BQ and OQ induced cell apoptosis by regulating the mitochondrial pathway and cell cycle arrest at the G2/M phase via inhibition of the Akt signaling pathway in AGS cells. Furthermore, BQ and OQ significantly increased the levels of reactive oxygen species (ROS) and this effect was blocked by the ROS scavenger NAC in AGS cells. BQ and OQ induced apoptosis by upregulating the protein expression of p38 and JNK and downregulating the levels of ERK and STAT3. Furthermore, expression levels of these proteins were also blocked after NAC treatment. These results demonstrated that BQ and OQ induced apoptosis and cell cycle arrest at the G2/M phase in AGS cells by stimulating ROS generation, which caused subsequent activation of MAPK, Akt and STAT3 signaling pathways. Thus, BQ and OQ may serve as potential therapeutic agents for the treatment of human gastric cancer.
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Affiliation(s)
- Hao Wang
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Ying-Hua Luo
- Department of Grass Science, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Gui-Nan Shen
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Xian-Ji Piao
- Department of Gynaecology and Obstetrics, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, Heilongjiang 163316, P.R. China
| | - Wan-Ting Xu
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Yi Zhang
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Jia-Ru Wang
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Yu-Chao Feng
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Jin-Qian Li
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Yu Zhang
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Tong Zhang
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Shi-Nong Wang
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Hui Xue
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Hong-Xing Wang
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Chang-Yuan Wang
- Department of Food Science and Engineering, College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Cheng-Hao Jin
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
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Courtois S, Lehours P, Bessède E. The therapeutic potential of metformin in gastric cancer. Gastric Cancer 2019; 22:653-662. [PMID: 30900101 DOI: 10.1007/s10120-019-00952-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 03/11/2019] [Indexed: 02/07/2023]
Abstract
Metformin is a biguanide molecule used since 1957 to treat type 2 diabetes patients. In addition to its hypoglycemic effects, epidemiological studies have shown that metformin can be associated with a decrease in cancer development risk in diabetic populations. Thus, since 2005 this molecule is largely studied for its antitumoural properties in different types of cancer. The potential antitumoural effect of metformin in gastric cancer has been poorly studied. Here, we detailed the different described mechanisms implicated in the antitumoural effect of metformin in gastric cancer, from the signalling pathways to the functional effects on gastric cancer cell lines and gastric cancer stem cells.
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Affiliation(s)
- Sarah Courtois
- INSERM, Univ. Bordeaux, UMR1053 Bordeaux Research In Translational Oncology, BaRITOn, 33000, Bordeaux, France.
| | - Philippe Lehours
- INSERM, Univ. Bordeaux, UMR1053 Bordeaux Research In Translational Oncology, BaRITOn, 33000, Bordeaux, France.,French National Reference Center for Campylobacters and Helicobacters in Bordeaux (CNRCH), University Hospital of Bordeaux, Bordeaux, France
| | - Emilie Bessède
- INSERM, Univ. Bordeaux, UMR1053 Bordeaux Research In Translational Oncology, BaRITOn, 33000, Bordeaux, France.,French National Reference Center for Campylobacters and Helicobacters in Bordeaux (CNRCH), University Hospital of Bordeaux, Bordeaux, France
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Luo Z, Chen W, Wu W, Luo W, Zhu T, Guo G, Zhang L, Wang C, Li M, Shi S. Metformin promotes survivin degradation through AMPK/PKA/GSK-3β-axis in non-small cell lung cancer. J Cell Biochem 2019; 120:11890-11899. [PMID: 30793366 DOI: 10.1002/jcb.28470] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 12/28/2018] [Accepted: 01/09/2019] [Indexed: 01/24/2023]
Abstract
Metformin, a first-line antidiabetic drug, has been reported with anticancer activities in many types of cancer. However, its molecular mechanisms remain largely unknown. As a member of inhibitor of apoptosis proteins, survivin plays an important role in the regulation of cell death. In the present study, we investigated the role of survivin in metformin-induced anticancer activity in non-small cell lung cancer in vitro. Metformin mainly induced apoptotic cell death in A549 and H460 cell lines. It remarkably suppressed the expression of survivin, decreased the stability of this protein, then promoted its proteasomal degradation. Moreover, metformin greatly suppressed protein kinase A (PKA) activity and induced its downstream glycogen synthase kinase 3β (GSK-3β) activation. PKA activators, both 8-Br-cAMP and forskolin, significantly increased the expression of survivin. Consistently both GSK-3β inhibitor LiCl and siRNA restored the expression of survivin in lung cancer cells. Furthermore, metformin induced adenosine 5'-monophosphate-activated protein kinase (AMPK) activation. Suppression of the activity of AMPK with Compound C reversed the degradation of survivin induced by metformin, and meanwhile, restored the activity of PKA and GSK-3β. These results suggest that metformin kills lung cancer cells through AMPK/PKA/GSK-3β-axis-mediated survivin degradation, providing novel insights into the anticancer effects of metformin.
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Affiliation(s)
- Zhuang Luo
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, P.R. China
| | - Wei Chen
- Department of Pathophysiology in School of Basic Medical Science, North Sichuan Medical College, Nanchong, P.R. China
| | - Wenjuan Wu
- Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, P.R. China
| | - Wei Luo
- Department of Pulmonary and Critical Care Medicine, The People's Hospital of Leshan, Leshan, P.R. China
| | - Tingting Zhu
- Department of Dermatology, The First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Gang Guo
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Liyan Zhang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, P.R. China
| | - Chu Wang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, P.R. China
| | - Min Li
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, P.R. China
| | - Shaoqing Shi
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, P.R. China
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Ye J, Qi L, Chen K, Li R, Song S, Zhou C, Zhai W. Metformin induces TPC-1 cell apoptosis through endoplasmic reticulum stress-associated pathways in vitro and in vivo. Int J Oncol 2019; 55:331-339. [PMID: 31180536 DOI: 10.3892/ijo.2019.4820] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 05/23/2019] [Indexed: 11/05/2022] Open
Abstract
Thyroid cancer is among the most common types of malignant tumor of the endocrine system. The role of metformin in the inhibition of cancer cell proliferation and induction of apoptosis is widely accepted. The present study explored the effect and the underlying mechanisms of metformin on human thyroid cancer TPC‑1 cells. Following treatment of TPC‑1 cells with different concentrations of metformin, cell proliferation and apoptosis were analyzed by cell counting kit‑8 (CCK‑8) assay and flow cytometry, respectively. Reverse transcription‑quantitative PCR and western blotting were used to detect alterations in the mRNA and protein expression levels, respectively, for heat shock protein family A member 5 (HSPA5, also known as Bip), DNA damage‑inducible transcript 3 (DDIT3, also known as CHOP) and caspase‑12. The results demonstrated that treatment with metformin inhibited proliferation and induced apoptosis in a concentration and time‑dependent manner. In addition, treatment with metformin increased the expression of Bip, CHOP and caspase‑12 in vitro, activating endoplasmic reticulum (ER) stress. Thapsigargin treatment enhanced the apoptosis induced by metformin. Inhibition of ER stress by 4‑phenylbutyrate reversed the metformin‑induced apoptosis. Finally, treatment with metformin inhibited thyroid cancer growth and increased the expression of Bip and CHOP in a TPC‑1 cell xenograft model. These results indicated that metformin increased the apoptotic rate of thyroid cancer cells via ER stress‑associated mechanisms.
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Affiliation(s)
- Jianwen Ye
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Lei Qi
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Kunlun Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Renfeng Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Shengping Song
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Chuang Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Wenlong Zhai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Cheng Z, Shao X, Xu M, Wang J, Kuai X, Zhang L, Wu J, Zhou C, Mao J. Rab1A promotes proliferation and migration abilities via regulation of the HER2/AKT-independent mTOR/S6K1 pathway in colorectal cancer. Oncol Rep 2019; 41:2717-2728. [PMID: 30896866 PMCID: PMC6448090 DOI: 10.3892/or.2019.7071] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 03/07/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal carcinoma (CRC) is one of the most common malignancies worldwide and the second leading cause of cancer-related deaths in the US. Recently, Rab1A has been reported to be an activator of mTORC1 and p-S6K1, which is downstream of mTORC1. However, the association between Rab1A and p-S6K1 in CRC remains elusive. In the present study, we first demonstrated that Rab1A was overexpressed in CRC tissues and Rab1A overexpression was positively related to lymph node invasion, degree of differentiation, venous invasion and tumor-node-metastasis (TNM) stage. In both TNM stage I–II and III–IV patients, Rab1A-positive patients had a shorter survival time than Rab1A-negative patients. Furthermore, in univariate and multivariate analyses, only Rab1A expression was verified as an independent prognostic factor for survival in CRC patients. The level of p-S6K1 was markedly high in CRC tissues and Rab1A expression level had a positive association with p-S6K1 level. In addition, high levels of both Rab1A and p-S6K1 were associated with a poorer prognosis compared with low expression of either Rab1A or p-S6K1 level. Moreover, high levels of both Rab1A and p-S6K1 were associated with a poorer prognosis than patients with high levels of either Rab1A or p-S6K1 alone. Finally, knockdown of Rab1A expression inhibited migration and proliferation of SW480 and HCT116 cell lines by targeting regulation of p-S6K1. Thus, our findings indicate that Rab1A plays an important role in CRC and may provide a therapeutic target for CRC, particularly for mTORC1-targeted therapy-resistant cancers.
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Affiliation(s)
- Zhengwu Cheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Xinyu Shao
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215006, P.R. China
| | - Menglin Xu
- Department of Oncology, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Junfeng Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Xiaoyi Kuai
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215006, P.R. China
| | - Liping Zhang
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215006, P.R. China
| | - Jian Wu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Chunli Zhou
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215006, P.R. China
| | - Jiading Mao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241000, P.R. China
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48
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An ssDNA aptamer selected by Cell-SELEX for the targeted imaging of poorly differentiated gastric cancer tissue. Talanta 2019; 199:634-642. [PMID: 30952308 DOI: 10.1016/j.talanta.2019.03.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 02/15/2019] [Accepted: 03/02/2019] [Indexed: 12/29/2022]
Abstract
Gastric cancer (GC) is associated with high morbidity and mortality rates worldwide. Poorly differentiated GC predicts a poor prognosis and is related to patients' response to chemotherapy and targeted therapy. Therefore, it is very important to accurately evaluate the tumour differentiation status for the treatment of poorly differentiated GC. To develop a molecular probe to analyse poorly differentiated GC, we selected aptamers against poorly differentiated GC by subtractive Cell-SELEX using the poorly differentiated GC cell line BGC-823 as the target and the moderately differentiated GC cell line SGC-7901 as the negative control. After 15 rounds of selection, aptamer PDGC21 exhibited the highest affinity, and the Kd value of the truncated aptamer PDGC21-T was 35.2 ± 1.1 nM. Aptamer PDGC21-T not only specifically bound to the target cells but also bound to other poorly differentiated GC cells. When combined with fluorescent nanoparticle quantum dots (QDs), the PDGC21-T-QD probe could distinguish poorly differentiated GC cells in mixed culture cells and clinical specimens. Furthermore, in a tissue microarray containing 15 cases from patients, there was a higher positive rate in GC tissues compared with adjacent normal tissues; in poorly differentiated tissues, in particular, the fluorescence signal was significantly higher than that in well/moderately differentiated tissues. Therefore, aptamer PDGC21-T holds great potential for use as a molecular imaging probe for the detection of poorly differentiated GC, which is of great significance for diagnosis and treatment.
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49
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Serrano D, Bonanni B, Brown K. Therapeutic cancer prevention: achievements and ongoing challenges - a focus on breast and colorectal cancer. Mol Oncol 2019; 13:579-590. [PMID: 30690875 PMCID: PMC6396378 DOI: 10.1002/1878-0261.12461] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 01/16/2019] [Accepted: 01/19/2019] [Indexed: 12/14/2022] Open
Abstract
The constant increase of cancer incidence and the huge costs of new treatments make cancer prevention a crucial goal in order to maintain sustainable public health systems across the world. Carcinogenesis is a multistep process, which allows time for active intervention with natural or synthetic agents to stop or reverse the pathological process. Cancer prevention medicine can be considered to be treatment of premalignant cells or preneoplastic conditions. Clearly such interventions require well‐defined risk classification so that personalized strategies and specific treatments can be applied to cohorts with a documented increased cancer risk, and not to the general population as a whole. Further development of these strategies in an efficient and timely manner requires investment in the discovery and validation of surrogate cancer biomarkers with both prognostic and predictive value to detect and monitor the efficacy of interventions in clinical trials and beyond. In the field of cancer prevention medicine, breast and colon cancer demonstrates the strongest clinical evidence that pharmacological intervention can lower cancer risk. Here, we offer an overview of the major clinical achievements for these cancers and the critical issues to improve implementation and clinical uptake of efficacious therapies, as well as further developments needed in the field of preventive medicine.
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Affiliation(s)
- Davide Serrano
- Division of Cancer Prevention and Genetics, European Institute of Oncology IRCCS, Milan, Italy
| | - Bernardo Bonanni
- Division of Cancer Prevention and Genetics, European Institute of Oncology IRCCS, Milan, Italy
| | - Karen Brown
- Leicester Cancer Research Centre, University of Leicester, UK
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50
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Tuo L, Xiang J, Pan X, Hu J, Tang H, Liang L, Xia J, Hu Y, Zhang W, Huang A, Wang K, Tang N. PCK1 negatively regulates cell cycle progression and hepatoma cell proliferation via the AMPK/p27 Kip1 axis. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:50. [PMID: 30717766 PMCID: PMC6360696 DOI: 10.1186/s13046-019-1029-y] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 01/07/2019] [Indexed: 01/08/2023]
Abstract
Background Altered glucose metabolism endows tumor cells with metabolic flexibility for biosynthesis requirements. Phosphoenolpyruvate carboxykinase 1 (PCK1), a key enzyme in the gluconeogenesis pathway, is downregulated in hepatocellular carcinoma (HCC) and predicts poor prognosis. Overexpression of PCK1 has been shown to suppress liver tumor growth, but the underlying mechanism remains unclear. Methods mRNA and protein expression patterns of PCK1, AMPK, pAMPK, and the CDK/Rb/E2F pathway were determined using qRT-PCR and western blotting. Cell proliferation ability and cell cycle were assessed by MTS assay and flow cytometric analysis. The effect of PCK1 on tumor growth was examined in xenograft implantation models. Results Both gain and loss-of-function experiments demonstrated that PCK1 deficiency promotes hepatoma cell proliferation through inactivation of AMPK, suppression of p27Kip1 expression, and stimulation of the CDK/Rb/E2F pathway, thereby accelerating cell cycle transition from the G1 to S phase under glucose-starved conditions. Overexpression of PCK1 reduced cellular ATP levels and enhanced AMPK phosphorylation and p27Kip1 expression but decreased Rb phosphorylation, leading to cell cycle arrest at G1. AMPK knockdown significantly reversed G1-phase arrest and growth inhibition of PCK1-expressing SK-Hep1 cells. In addition, the AMPK activator metformin remarkably suppressed the growth of PCK1-knockout PLC/PRF/5 cells and inhibited tumor growth in an orthotropic HCC mouse model. Conclusion This study revealed that PCK1 negatively regulates cell cycle progression and hepatoma cell proliferation via the AMPK/p27Kip1 axis and supports a potential therapeutic and protective effect of metformin on HCC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1029-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lin Tuo
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Jin Xiang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Xuanming Pan
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Jieli Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Hua Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Li Liang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Jie Xia
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Yuan Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Wenlu Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Ailong Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China.
| | - Kai Wang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China.
| | - Ni Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China.
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