二甲双胍抗肿瘤机制的研究进展

Advances of the anti‑tumor research of metformin

二甲双胍通过减少肝脏葡萄糖的合成及肠道葡萄糖的吸收达到降低糖尿病患者空腹及餐后血糖的目的,主要用于肥胖型2型糖尿病。而近年来的研究发现,二甲双胍还可抑制肿瘤细胞的增殖、迁移和侵袭、抑制肿瘤血管生成、干扰肿瘤细胞周期并诱导细胞凋亡、诱导细胞分化等发挥抗肿瘤作用。它主要通过单磷酸腺苷蛋白激酶(AMPK)依赖性和非AMPK依赖性机制,其中二甲双胍激活AMPK的途径又分为直接途径和间接途径两种。两种机制可单独发挥作用也可交叉发挥作用,通过影响肿瘤细胞和免疫细胞的信号转导通路和能量代谢,参与改善乏氧和免疫抑制的肿瘤免疫微环境,以及通过调节肠道菌群改善机体代谢和免疫功能,发挥抗肿瘤作用,抑制肿瘤发生、发展,以达到治疗肿瘤的目的。目前已有若干临床试验采取不同的治疗方式与二甲双胍联用,并取得了一定的成绩。现就二甲双胍对肿瘤细胞、肿瘤微环境、肠道菌群的影响及其抗肿瘤的相关临床试验四个方面展开综述。

Metformin is a classic hypoglycemic drug.It reduces fasting and postprandial hyperglycemia in diabetic patients by reducing liver glucose synthesis and intestinal glucose absorption.It is mainly aimed at obese patients with type 2 diabetes.Recent studies have shown that metformin can also inhibit the proliferation,migration,invasion of tumor cells and inhibit tumor angiogenesis.Meanwhile it also can induce apoptosis and induce cell differentiation.Metformin affects the signal transduction pathway and energy metabolism of tumor cells and immune cells through adenosine monophosphate protein kinase(AMPK)⁃dependent which is divided into direct and indirect ways and non⁃AMPK⁃dependent mechanisms,participates in improving the tumor immune microenvironment of hypoxia and immunosuppression,improves metabolism and immune function by regulating intestinal flora,and exerts an anti⁃tumor effect and then achieve the purpose of treating tumors.There have been many clinical trials,which have adopted different treatment measures in combination with metformin,and have achieved certain results.This article reviews the effects of metformin on tumor cells,tumor microenvironment,intestinal flora and the related clinical trials of metformin against tumor.