Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models
Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models
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在体外和体内异种移植模型中，二甲双胍显示出抗骨髓瘤活性以及与地塞米松的协同作用。
DOI：
10.1016/j.canlet.2014.09.050
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发表时间：
2015-01-28
期刊：
影响因子：
9.7
通讯作者：
Cai, Zhen
中科院分区：
文献类型：
--
作者：
Zi, Fu-Ming;He, Jing-Song;Cai, Zhen
流行病学研究和荟萃分析表明，2型糖尿病（T2 DM）患者的恶性肿瘤（包括骨髓瘤）发生率较高。二甲双胍是一种广泛使用的抗糖尿病药物。近年来研究表明二甲双胍对多种肿瘤细胞系具有直接的抗癌活性，主要通过激活AMP活化蛋白激酶（AMPK）或降低血胰岛素水平。在本研究中，我们研究了二甲双胍是否在体外和体内异种移植模型中发挥抗骨髓瘤作用，并探讨了潜在的机制。我们发现二甲双胍可以通过诱导细胞凋亡和细胞周期阻滞在G 0/G1期来抑制MM细胞的增殖。Western blot显示二甲双胍激活半胱天冬酶3、半胱天冬酶9、PARP-1、巴克和p21，并灭活Mcl-1、HIAP-1、细胞周期蛋白D1、CDK 4和CDK 6。二甲双胍抑制胰岛素生长因子-I受体（IGF-IR）、磷脂酰肌醇3-激酶（PI 3 K）、蛋白激酶B（PKB/AKT）和雷帕霉素下游哺乳动物靶蛋白（mTOR）的表达。IGF-I阻断二甲双胍诱导的MM细胞凋亡和PI 3 K/AKT/mTOR信号通路的再激活。在体外和体内，尤其是在MM. 1 S细胞中，二甲双胍还表现出与地塞米松而不是硼替佐米根除MM细胞的协同活性。我们得出的结论是，二甲双胍通过IGF-1 R/P13 K/AKT/mTOR信号通路抑制MM细胞增殖。二甲双胍和地塞米松联合治疗可能是MM治疗的一种选择。(C)2014爱思唯尔爱尔兰有限公司版权所有。
Epidemiologic studies and meta-analyses have suggested that patients with type 2 diabetes mellitus (T2DM) have a higher incidence of malignancies, including myeloma. Metformin is a widely prescribed antidiabetic drug. Recently, researchers have shown that metformin has direct anticancer activity against many tumor cell lines, mainly through activating AMP-activated protein kinase (AMPK) or reducing the blood insulin level. In the present study, we investigated whether metformin exerts an anti-myeloma effect in in vitro and in vivo xenograft models and explored the underlying mechanism. We found that metformin can inhibit proliferation of MM cells by inducing apoptosis and cell cycle arrest in the G0/G1 phase. Western blot showed that metformin activated caspase 3, caspase 9, PARP-1, Bak, and p21 and inactivated Mcl-1, HIAP-1, cyclin D1, CDK4, and CDK6. Metformin inhibited the expression of insulin growth factor-I receptor (IGF-IR), and phosphatidyl inositol 3-kinase (PI3K), protein kinase B (PKB/AKT) and the downstream mammalian target of rapamycin (mTOR). IGF-I blocked metformin-induced MM cell apoptosis and reactivation of the PI3K/AKT/mTOR signaling pathway. Metformin also demonstrated synergistic activity with dexamethasone but not bortezomib to eradicate MM cells in vitro and in vivo, especially in MM.1S cells. We conclude that metformin inhibits MM cell proliferation through the IGF-1R/P13K/AKT/mTOR signaling pathway. Metformin and dexamethasone combination therapy may be an option for MM treatment. (C) 2014 Elsevier Ireland Ltd. All rights reserved.