| Metformin induces apoptosis of pancreatic cancer cells. | |
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MedLine Citation:
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PMID: 19084933 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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AIM: To assess the role and mechanism of metformin in inducing apoptosis of pancreatic cancer cells. METHODS: The human pancreatic cancer cell lines ASPC-1, BxPc-3, PANC-1 and SW1990 were exposed to metformin. The inhibition of cell proliferation and colony formation via apoptosis induction and S phase arrest in pancreatic cancer cell lines of metformin was tested. RESULTS: In each pancreatic cancer cell line tested, metformin inhibited cell proliferation in a dose dependent manner in MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays). Flow cytometric analysis showed that metformin reduced the number of cells in G1 and increased the percentage of cells in S phase as well as the apoptotic fraction. Enzymelinked immunosorbent assay (ELISA) showed that metformin induced apoptosis in all pancreatic cancer cell lines. In Western blot studies, metformin induced poly-ADP-ribose polymerase (PARP) cleavage (an indicator of caspase activation) in all pancreatic cancer cell lines. The general caspase inhibitor (VAD-fmk) completely abolished metformin-induced PARP cleavage and apoptosis in ASPC-1 BxPc-3 and PANC-1, the caspase-8 specific inhibitor (IETD-fmk) and the caspase-9 specific inhibitor (LEHD-fmk) only partially abrogated metformin-induced apoptosis and PARP cleavage in BxPc-3 and PANC-1 cells. We also observed that metformin treatment dramatically reduced epidermal growth factor receptor (EGFR) and phosphorylated mitogen activated protein kinase (P-MAPK) in both a time- and dose-dependent manner in all cell lines tested. CONCLUSION: Metformin significantly inhibits cell proliferation and apoptosis in all pancreatic cell lines. And the metformin-induced apoptosis is associated with PARP cleavage, activation of caspase-3, -8, and -9 in a time- and dose-dependent manner. Hence, both caspase-8 and -9-initiated apoptotic signaling pathways contribute to metformin-induced apoptosis in pancreatic cell lines. |
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Authors:
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Luo-Wei Wang; Zhao-Shen Li; Duo-Wu Zou; Zhen-Dong Jin; Jun Gao; Guo-Ming Xu |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: World journal of gastroenterology : WJG Volume: 14 ISSN: 1007-9327 ISO Abbreviation: World J. Gastroenterol. Publication Date: 2008 Dec |
Date Detail:
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Created Date: 2008-12-16 Completed Date: 2009-05-19 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 100883448 Medline TA: World J Gastroenterol Country: China |
Other Details:
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Languages: eng Pagination: 7192-8 Citation Subset: IM |
Affiliation:
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Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenocarcinoma
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metabolism,
pathology* Apoptosis / drug effects* Caspase 8 / metabolism Caspase 9 / metabolism Cell Cycle / drug effects Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Dose-Response Relationship, Drug Humans Hypoglycemic Agents / pharmacology* Metformin / pharmacology* Pancreatic Neoplasms / metabolism, pathology* Receptor, Epidermal Growth Factor / metabolism Signal Transduction / drug effects |
| Chemical | |
Reg. No./Substance:
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0/Hypoglycemic Agents; 657-24-9/Metformin; EC 2.7.10.1/EGFR protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 3.4.22.-/Caspase 8; EC 3.4.22.-/Caspase 9 |
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