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].
参考文献:
[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]。
| Cell experiment [1]: | |
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Cell lines |
Six breast cancer cell lines, including MCF7, BT20, T47D, MDA-MB-453, and MDA-MB-231 |
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Preparation Method |
Human breast cancer cells were plated into 35 mm dishes. After one day cells were treated with metformin at the indicated concentrations or the same volume of sterilized water,incubated with metformin for 1, 2 or 3 days. |
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Reaction Conditions |
8 mM for 1, 2 or 3 days |
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Applications |
Five of six breast cancer cell lines, including MCF7, BT20, T47D, MDA-MB-453, and MDA-MB-474, underwent growth arrest after metformin treatment. |
| Animal experiment [2]: | |
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Animal models |
female FVB/N HER-2/neu mice |
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Preparation Method |
Mice of the first group were given metformin with drinking water (100 mg/kg) for five consecutive days every month for 12 months, whereas the mice of the second group were given tap water without metformin and served as a control. |
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Dosage form |
100 mg/kg, oral |
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Applications |
One control mouse (3%) survived the age of 10 months whereas 9 mice (28%) survived this age in metformin-treated group |
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参考文献: [1]: 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. |
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