Antiproliferative action of metformin in human lung cancer cell lines
Antiproliferative action of metformin in human lung cancer cell lines
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DOI：
10.3892/or.2012.1763
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发表时间：
2012-07-01
期刊：
影响因子：
4.2
通讯作者：
Tatsumi, Koichiro
中科院分区：
文献类型：
--
作者：
Ashinuma, Hironori;Takiguchi, Yuichi;Tatsumi, Koichiro
口服降糖药二甲双胍具有抗癌特性，可能是通过单磷酸腺苷活化蛋白激酶激活的。在本研究中，通过克隆性和细胞存活试验评估生长抑制作用，通过Hoechst染色评估细胞凋亡诱导作用，以及暴露于二甲双胍后caspase活性和细胞周期改变，并在体外阐明了二甲双胍与顺铂在四种人肺癌细胞系（鳞状、腺状、大细胞和小细胞癌）中的相互作用。二甲双胍对所有细胞系的克隆性和细胞增殖均有抑制作用。这种抑制作用并非针对癌细胞，因为在未转化的人间皮细胞系和小鼠成纤维细胞系中也观察到这种抑制作用。只有长时间（10天）暴露在二甲双胍中才能观察到细胞的克隆性抑制作用，并且通过增加剂量抑制增殖后获得的存活分数在约0.1-0.3时达到平台，表明二甲双胍具有细胞抑制特性。二甲双胍仅在小细胞癌细胞系中诱导显著的凋亡。四种细胞系均有G0/G1期细胞周期积累的趋势。顺铂以剂量依赖的方式严重拮抗二甲双胍的生长抑制作用，甚至在三种细胞系中逆转了这种作用，但在腺癌细胞系中没有。目前使用不同组织学类型的人肺癌细胞系在体外获得的数据说明了二甲双胍的细胞抑制性质及其对顺铂的细胞保护特性。
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 metform in 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.