title: The antidiabetic drug metformin inhibits the proliferation of bladder cancer cells in vitro and in vivo.
abstract: Recent studies suggest that metformin, a widely used antidiabetic agent, may reduce cancer risk and improve prognosis of certain malignancies. However, the mechanisms for the anti-cancer effects of metformin remain uncertain. In this study, we investigated the effects of metformin on human bladder cancer cells and the underlying mechanisms. Metformin significantly inhibited the proliferation and colony formation of 5637 and T24 cells in vitro; specifically, metformin induced an apparent cell cycle arrest in G0/G1 phases, accompanied by a strong decrease of cyclin D1, cyclin-dependent kinase 4 (CDK4), E2F1 and an increase of p21waf-1. Further experiments revealed that metformin activated AMP-activated protein kinase (AMPK) and suppressed mammalian target of rapamycin (mTOR), the central regulator of protein synthesis and cell growth. Moreover, daily treatment of metformin led to a substantial inhibition of tumor growth in a xenograft model with concomitant decrease in the expression of proliferating cell nuclear antigen (PCNA), cyclin D1 and p-mTOR. The in vitro and in vivo results demonstrate that metformin efficiently suppresses the proliferation of bladder cancer cells and suggest that metformin may be a potential therapeutic agent for the treatment of bladder cancer.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Xiong
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.forename: Shan
authors.initials: S
authors.lastname: Xu
authors.forename: Xinyang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Minimally Invasive Urology Center, Provincial Hospital Affiliated to Shandong University, Jinan 250021, China. dalinhexjtu@yahoo.com.cn.
authors.forename: Dalin
authors.initials: D
authors.lastname: He
authors.affiliation: Minimally Invasive Urology Center, Provincial Hospital Affiliated to Shandong University, Jinan 250021, China. jinxunbo@163.com.
authors.forename: Xunbo
authors.initials: X
authors.lastname: Jin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014183:Transplantation, Heterologous; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D007004:Hypoglycemic Agents; D018809:Proliferating Cell Nuclear Antigen; D019938:Cyclin D1; D008687:Metformin; D058570:TOR Serine-Threonine Kinases; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D055372:AMP-Activated Protein Kinases