Metformin Amplifies Chemotherapy-Induced AMPK Activation and Antitumoral Growth
Metformin Amplifies Chemotherapy-Induced AMPK Activation and Antitumoral Growth
复制标题
DOI：
10.1158/1078-0432.ccr-10-2243
复制
发表时间：
2011-06-15
影响因子：
11.5
通讯作者：
Carvalheira, Jose B. C.
中科院分区：
文献类型：
--
作者：
Rocha, Guilherme Z.;Dias, Marilia M.;Carvalheira, Jose B. C.
目的：二甲双胍是一种广泛使用的抗糖尿病药物，其通过激活AMP活化蛋白激酶（AMPK）和减少mTOR信号传导介导的抗癌作用已变得值得注意。化疗产生遗传毒性应激并诱导p53活性，其可与AMPK/mTOR通路交叉。在此，我们调查是否二甲双胍和紫杉醇的组合具有在癌细胞line.Experimental设计的效果：人类肿瘤异种移植到严重的联合免疫缺陷（SCID）小鼠和癌细胞系进行治疗，只有紫杉醇或只有二甲双胍，或两种药物的组合。Western印迹，流式细胞术，免疫组化，然后被用来表征不同treatment.Results的效果：本文所呈现的结果表明，除了二甲双胍紫杉醇导致定量增强分子信号通过AMPK和随后的有效抑制mTOR信号通路。二甲双胍和紫杉醇的治疗导致在细胞周期的G（2）-M期的细胞数量增加，并降低肿瘤的生长和增加细胞凋亡的荷瘤小鼠，当与单独的药物treatment.Conclusion：我们提供了证据二甲双胍和紫杉醇诱导的信号在AMPK水平的收敛。这一机制显示了不同的药物如何协同增强抗生长信号，并表明二甲双胍对AMPK的靶向激活可能是癌症治疗中一个令人信服的盟友。临床癌症研究; 17（12）; 3993-4005。(C)2011年AACR。
Purpose: Metformin is a widely used antidiabetic drug whose anticancer effects, mediated by the activation of AMP-activated protein kinase (AMPK) and reduction of mTOR signaling, have become noteworthy. Chemotherapy produces genotoxic stress and induces p53 activity, which can cross-talk with AMPK/mTOR pathway. Herein, we investigate whether the combination of metformin and paclitaxel has an effect in cancer cell lines.Experimental Design: Human tumors were xenografted into severe combined immunodeficient (SCID) mice and the cancer cell lines were treated with only paclitaxel or only metformin, or a combination of both drugs. Western blotting, flow cytometry, and immunohistochemistry were then used to characterize the effects of the different treatments.Results: The results presented herein show that the addition of metformin to paclitaxel leads to quantitative potentialization of molecular signaling through AMPK and a subsequent potent inhibition of the mTOR signaling pathway. Treatment with metformin and paclitaxel resulted in an increase in the number of cells arrested in the G(2)-M phase of the cell cycle, and decreased the tumor growth and increased apoptosis in tumor-bearing mice, when compared with individual drug treatments.Conclusion: We have provided evidence for a convergence of metformin and paclitaxel induced signaling at the level of AMPK. This mechanism shows how different drugs may cooperate to augment antigrowth signals, and suggests that target activation of AMPK by metformin may be a compelling ally in cancer treatment. Clin Cancer Res; 17(12); 3993-4005. (C) 2011 AACR.