title: Antiproliferative action of metformin in human lung cancer cell lines.
abstract: The oral antidiabetic agent metformin has anticancer properties, probably via adenosine monophosphate-activated protein kinase activation. In the present study, growth inhibition was assessed by a clonogenic and by a cell survival assay, apoptosis induction was assessed by Hoechst staining and caspase activities and cell cycle alteration after exposure to metformin, and the interaction of metformin with cisplatin in vitro were elucidated in four human lung cancer cell lines representing squamous, adeno-, large cell and small cell carcinoma. Clonogenicity and cell proliferation were inhibited by metformin in all the cell lines examined. This inhibitory effect was not specific to cancer cells because it was also observed in a non-transformed human mesothelial cell line and in mouse fibroblast cell lines. Inhibition of clonogenicity was observed only when the cells were exposed to metformin for a long period, (10 days) and the surviving fraction, obtained after inhibiting proliferation by increasing the dose, reached a plateau at approximately 0.1-0.3, indicating the cytostatic characteristics of metformin. Metformin induced significant apoptosis only in the small cell carcinoma cell line. A tendency of cell cycle accumulation at the G0/G1 phase was observed in all four cell lines. Cisplatin, in a dose-dependent manner, severely antagonized the growth inhibitory effect of metformin, and even reversed the effect in three cell lines but not in the adenocarcinoma cell line. The present data obtained using various histological types of human lung cancer cell lines in vitro illustrate the cytostatic nature of metformin and its cytoprotective properties against cisplatin.
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba                     University, Chiba, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Ashinuma
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takiguchi
authors.forename: Satoru
authors.initials: S
authors.lastname: Kitazono
authors.forename: Miyako
authors.initials: M
authors.lastname: Kitazono-Saitoh
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kitamura
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Chiba
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tada
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kurosu
authors.forename: Emiko
authors.initials: E
authors.lastname: Sakaida
authors.forename: Ikuo
authors.initials: I
authors.lastname: Sekine
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanabe
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
authors.forename: Osamu
authors.initials: O
authors.lastname: Yokosuka
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D041702:BALB 3T3 Cells; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004347:Drug Interactions; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms; D008687:Metformin / Q000494:pharmacology*; D051379:Mice
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D008687:Metformin; D020169:Caspases; D002945:Cisplatin