Metformin
(Synonyms: 二甲双胍; 1,1-Dimethylbiguanide) 目录号 : GC60245
二甲双胍（Metformin 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，导致癌细胞mTOR信号和蛋白质合成的减少。
Cas No.:657-24-9
Sample solution is provided at 25 µL, 10mM.
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- Purity: >95.00%
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| 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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References: [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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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]。
| Cas No. | 657-24-9 | SDF | |
| 别名 | 二甲双胍; 1,1-Dimethylbiguanide | ||
| Canonical SMILES | NC(NC(N(C)C)=N)=N | ||
| 分子式 | C4H11N5 | 分子量 | 129.16 |
| 溶解度 | DMSO: 100 mg/mL (774.23 mM); Water: 50 mg/mL (387.12 mM) | 储存条件 | 4°C, protect from light |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
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1 mg | 5 mg | 10 mg |
| 1 mM | 7.7423 mL | 38.7117 mL | 77.4234 mL |
| 5 mM | 1.5485 mL | 7.7423 mL | 15.4847 mL |
| 10 mM | 0.7742 mL | 3.8712 mL | 7.7423 mL |
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动物平均体重 | g | |
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动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
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2.
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Cellular and Molecular Mechanisms of Metformin Action
Endocr Rev 2021 Jan 28;42(1):77-96.PMID:32897388DOI:10.1210/endrev/bnaa023.
Metformin is a first-line therapy for the treatment of type 2 diabetes, due to its robust glucose-lowering effects, well-established safety profile, and relatively low cost. While Metformin has been shown to have pleotropic effects on glucose metabolism, there is a general consensus that the major glucose-lowering effect in patients with type 2 diabetes is mostly mediated through inhibition of hepatic gluconeogenesis. However, despite decades of research, the mechanism by which Metformin inhibits this process is still highly debated. A key reason for these discrepant effects is likely due to the inconsistency in dosage of Metformin across studies. Widely studied mechanisms of action, such as complex I inhibition leading to AMPK activation, have only been observed in the context of supra-pharmacological (>1 mM) Metformin concentrations, which do not occur in the clinical setting. Thus, these mechanisms have been challenged in recent years and new mechanisms have been proposed. Based on the observation that Metformin alters cellular redox balance, a redox-dependent mechanism of action has been described by several groups. Recent studies have shown that clinically relevant (50-100 μM) concentrations of Metformin inhibit hepatic gluconeogenesis in a substrate-selective manner both in vitro and in vivo, supporting a redox-dependent mechanism of Metformin action. Here, we review the current literature regarding Metformin's cellular and molecular mechanisms of action.
Metformin in 2019
JAMA 2019 May 21;321(19):1926-1927.PMID:31009043DOI:10.1001/jama.2019.3805.
Metformin is the first-line pharmacologic treatment for type 2 diabetes and the most commonly prescribed drug for this condition worldwide, either alone or in combination with insulin or other glucose-lowering therapies. Metformin is a biguanide, a drug class of herbal origin that has been widely used to treat diabetes since the 1950s., Two other biguanides were withdrawn from clinical use because they caused lactic acidosis. Metformin was also taken off the US market due to concerns over lactic acidosis, but it subsequently has been proven safe and effective in lowering glucose levels and was reintroduced in 1995. Optimal Metformin use requires clear understanding of its effects, dosing, safety, and alternatives.
Metformin: from mechanisms of action to therapies
Cell Metab 2014 Dec 2;20(6):953-66.PMID:25456737DOI:10.1016/j.cmet.2014.09.018.
Metformin is currently the first-line drug treatment for type 2 diabetes. Besides its glucose-lowering effect, there is interest in actions of the drug of potential relevance to cardiovascular diseases and cancer. However, the underlying mechanisms of action remain elusive. Convincing data place energy metabolism at the center of Metformin's mechanism of action in diabetes and may also be of importance in cardiovascular diseases and cancer. Metformin-induced activation of the energy-sensor AMPK is well documented, but may not account for all actions of the drug. Here, we summarize current knowledge about the different AMPK-dependent and AMPK-independent mechanisms underlying Metformin action.
Metformin--mode of action and clinical implications for diabetes and cancer
Nat Rev Endocrinol 2014 Mar;10(3):143-56.PMID:24393785DOI:10.1038/nrendo.2013.256.
Metformin has been the mainstay of therapy for diabetes mellitus for many years; however, the mechanistic aspects of Metformin action remained ill-defined. Recent advances revealed that this drug, in addition to its glucose-lowering action, might be promising for specifically targeting metabolic differences between normal and abnormal metabolic signalling. The knowledge gained from dissecting the principal mechanisms by which Metformin works can help us to develop novel treatments. The centre of Metformin's mechanism of action is the alteration of the energy metabolism of the cell. Metformin exerts its prevailing, glucose-lowering effect by inhibiting hepatic gluconeogenesis and opposing the action of glucagon. The inhibition of mitochondrial complex I results in defective cAMP and protein kinase A signalling in response to glucagon. Stimulation of 5'-AMP-activated protein kinase, although dispensable for the glucose-lowering effect of Metformin, confers insulin sensitivity, mainly by modulating lipid metabolism. Metformin might influence tumourigenesis, both indirectly, through the systemic reduction of insulin levels, and directly, via the induction of energetic stress; however, these effects require further investigation. Here, we discuss the updated understanding of the antigluconeogenic action of Metformin in the liver and the implications of the discoveries of Metformin targets for the treatment of diabetes mellitus and cancer.
Benefits of Metformin in Attenuating the Hallmarks of Aging
Cell Metab 2020 Jul 7;32(1):15-30.PMID:32333835DOI:10.1016/j.cmet.2020.04.001.
Biological aging involves an interplay of conserved and targetable molecular mechanisms, summarized as the hallmarks of aging. Metformin, a biguanide that combats age-related disorders and improves health span, is the first drug to be tested for its age-targeting effects in the large clinical trial-TAME (targeting aging by Metformin). This review focuses on Metformin's mechanisms in attenuating hallmarks of aging and their interconnectivity, by improving nutrient sensing, enhancing autophagy and intercellular communication, protecting against macromolecular damage, delaying stem cell aging, modulating mitochondrial function, regulating transcription, and lowering telomere attrition and senescence. These characteristics make Metformin an attractive gerotherapeutic to translate to human trials.