Metformin, a diabetes drug, eliminates tumor-initiating hepatocellular carcinoma cells.
Metformin, a diabetes drug, eliminates tumor-initiating hepatocellular carcinoma cells.
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DOI：
10.1371/journal.pone.0070010
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yokosuka O
中科院分区：
文献类型：
--
作者：
Saito T;Chiba T;Yuki K;Zen Y;Oshima M;Koide S;Motoyama T;Ogasawara S;Suzuki E;Ooka Y;Tawada A;Tada M;Kanai F;Takiguchi Y;Iwama A;Yokosuka O
二甲双胍作为糖尿病的口服药物已广泛使用约60年。有趣的是，最近的报告显示二甲双胍在包括肝细胞癌（HCC）在内的广泛恶性肿瘤中表现出抗肿瘤作用。在本研究中，我们研究了其对肿瘤起始HCC细胞的影响。二甲双胍以剂量依赖性方式抑制细胞生长并诱导细胞凋亡。流式细胞术分析显示二甲双胍治疗显著减少了肿瘤起始上皮细胞粘附分子（EpCAM）+ HCC细胞的数量。EpCAM+细胞的非粘附球体形成试验表明，二甲双胍不仅损害了它们的球体形成能力，而且损害了它们的自我更新能力。与此一致的是，球的免疫染色显示二甲双胍显著降低了肝干细胞标志物（如EpCAM和甲胎蛋白）阳性的组分细胞数量。在使用非肥胖糖尿病/严重联合免疫缺陷小鼠的异种移植物移植模型中，二甲双胍和/或索拉非尼治疗抑制了源自移植的HCC细胞的肿瘤的生长。值得注意的是，二甲双胍而不是索拉非尼的给药减少了EpCAM+细胞的数量并损害了它们的自我更新能力。据报道，二甲双胍通过磷酸化激活AMP活化蛋白激酶（AMPK）;然而，其对哺乳动物雷帕霉素靶蛋白（mTOR）通路的抑制作用不一定与其对EpCAM+肿瘤起始HCC细胞的抗肿瘤活性相关。这些结果表明，二甲双胍是一种有前途的治疗药物，用于消除肿瘤引发的HCC细胞，并表明其对AMPK/mTOR通路的抑制作用以外的未知功能。
Metformin has been widely used as an oral drug for diabetes mellitus for approximately 60 years. Interestingly, recent reports showed that metformin exhibited an anti-tumor action in a wide range of malignancies including hepatocellular carcinoma (HCC). In the present study, we investigated its impact on tumor-initiating HCC cells. Metformin suppressed cell growth and induced apoptosis in a dose-dependent manner. Flow cytometric analysis showed that metformin treatment markedly reduced the number of tumor-initiating epithelial cell adhesion molecule (EpCAM)+ HCC cells. Non-adherent sphere formation assays of EpCAM+ cells showed that metformin impaired not only their sphere-forming ability, but also their self-renewal capability. Consistent with this, immunostaining of spheres revealed that metformin significantly decreased the number of component cells positive for hepatic stem cell markers such as EpCAM and α-fetoprotein. In a xenograft transplantation model using non-obese diabetic/severe combined immunodeficient mice, metformin and/or sorafenib treatment suppressed the growth of tumors derived from transplanted HCC cells. Notably, the administration of metformin but not sorafenib decreased the number of EpCAM+ cells and impaired their self-renewal capability. As reported, metformin activated AMP-activated protein kinase (AMPK) through phosphorylation; however its inhibitory effect on the mammalian target of rapamycin (mTOR) pathway did not necessarily correlate with its anti-tumor activity toward EpCAM+ tumor-initiating HCC cells. These results indicate that metformin is a promising therapeutic agent for the elimination of tumor-initiating HCC cells and suggest as-yet-unknown functions other than its inhibitory effect on the AMPK/mTOR pathway.
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影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
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影响因子：
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作者：
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影响因子：
51.1
作者：
Cheng, Ann-Lii;Kang, Yoon-Koo;Guan, Zhongzhen
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Guan, Zhongzhen
影响因子：
4
作者：
Ji J;Wang XW
通讯作者：
Wang XW
DOI：
10.1111/j.1440-1746.2011.06664.x
发表时间：
2011-05-01
影响因子：
4.1
作者：
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通讯作者：
Wen, Chen-Fan