Metformin (1,1-Dimethylbiguanide) primarily mediate activation of AMPK, a serine/threonine protein kinase involved in regulating cellular energy metabolism, leading to a reduction in mTOR signaling and protein synthesis in cancer cells. Metformin activates AMPK by inhibiting complex I of the mitochondrial respiratory chain [1]. Metformin treatment reduced 4T1 cell viability with IC50: 16 mM, 24 h; 8 mM, 48 h; 4 mM, 72 h [2].
Metformin inhibited a variety of breast cancer cells growth regardless of oestrogen receptor (ER), PR, HER2 or p53 status [3]. Metformin induced unique responses in the triple-negative (ER, PR and HER2 negative) breast cancer cell line MDA-MB-231, leading to an S phase cell cycle arrest and then increase apoptosis [4]. Metformin may also be effective against ER-positive breast cancers by inhibiting aromatase expression in tumour stroma [5].
Orally administered metformin (at plasma levels (2.7-10.3 mM)) also reduced tobacco carcinogeninduced lung tumourigenesis (NNK) in mice (tumour burden reduced by 53%) [6]. Metformin treatment significantly delayed the appearance of mammary adenocarcinomas, reduced the size of tumours and prolonged the lifespan of MMTV-Her2/Neu mice [7].
Metformin is indicated for treatment of hyperglycemia in type 2 diabetes and improves glycemic control without inducing hypoglycemia or weight gain [8]. Metformin can cross though the blood-brain barrier and induces cell autophagy [9].
References:
[1]. Brunmair B, Staniek K, Gras F, Scharf N, Althaym A, Clara R, Roden M, Gnaiger E, Nohl H, Waldhausl W, et al. 2004 Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 53 1052-1059.
[2]. A. Farahi, M.R. Abedini, H. Javdani, L. Arzi, E. Chamani, R. Farhoudi, et al. Crocin and metformin suppress metastatic breast cancer progression via VEGF and MMP9 downregulations: in vitro and in vivo studies.Mol. Cell. Biochem. (2021), pp. 1-11
[3]. Zhuang?Y, Miskimins?WK.?Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1. J Mol Signal?2008;3:18.
[4]. Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, Lind SE & Thor AD. 2009. Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle 8 2031-2040.
[5]. Deng XS, Wang S, Deng A, Liu B, Edgerton SM, Lind SE, Wahdan-Alaswad R & Thor AD 2012 Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle 11 367-376.
[6]. Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD & Dennis PA 2010 Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prevention Research 3 1066-1076.
[7]. Anisimov?VN, Berstein?LM, Egormin?PA, Piskunova?TS, Popovich?IG, Zabezhinski?MA, Kovalenko?IG, Poroshina?TE, Semenchenko?AV, Provinciali?M, Re?F, Franceschi?C: Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol?2005;?40: 685-693
[8]. Flory, J. & Lipska, K. Metformin in 2019. JAMA321, 1926-1927 (2019).
[9]. Soraya H, et al. Acute treatment with metformin improves cardiac function following isoproterenol induced myocardial infarction in rats. Pharmacol Rep. 2012;64(6):1476-84.
二甲双胍（1,1-二甲基双胍）主要介导 AMPK 的激活,AMPK 是一种参与调节细胞能量代谢的丝氨酸/苏氨酸蛋白激酶,可导致癌细胞中 mTOR 信号传导和蛋白质合成的减少。二甲双胍通过抑制线粒体呼吸链的复合物 I 激活 AMPK [1]。二甲双胍治疗降低 4T1 细胞活力,IC50:16 mM,24 小时； 8 毫米,48 小时； 4 mM,72 h [2]。
无论雌激素受体 (ER)、PR、HER2 或 p53 状态如何,二甲双胍均能抑制多种乳腺癌细胞的生长[ 3]。二甲双胍在三阴性（ER、PR 和 HER2 阴性）乳腺癌细胞系 MDA-MB-231 中诱导独特的反应,导致 S 期细胞周期停滞,然后增加细胞凋亡[4]。二甲双胍还可以通过抑制肿瘤间质中的芳香化酶表达来有效对抗 ER 阳性乳腺癌[5]。
口服二甲双胍（血浆水平 (2.7-10.3 mM)）还减少了小鼠烟草致癌物诱发的肺部肿瘤发生 (NNK)（肿瘤负担降低了 53%）[6]。二甲双胍治疗显着延缓了 MMTV-Her2/Neu 小鼠乳腺癌的出现,缩小了肿瘤的大小并延长了其寿命[7]。
二甲双胍适用于治疗2 型糖尿病患者的高血糖症,并在不引起低血糖或体重增加的情况下改善血糖控制[8]。二甲双胍可穿过血脑屏障并诱导细胞自噬[9]。