MATE2表达与癌细胞对二甲双胍的反应有关。

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Chowdhury S, Yung E, Pintilie M, Muaddi H, Chaib S, Yeung M, Fusciello M, Sykes J, Pitcher B, Hagenkort A, McKee T, Vellanki R, Chen E, Bristow RG, Wouters BG, Koritzinsky M

MATE2表达与癌细胞对二甲双胍的反应有关。

PLoS One, 2016年12月13日;11(12):e0165214。doi: 10.1371 / journal.pone.0165214。eCollection 2016。

PubMed ID

27959931 (PubMed视图

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摘要

背景:人们对将常用的抗糖尿病药物二甲双胍用于癌症治疗非常感兴趣。二甲双胍的细胞内摄取和保留受有机阳离子转运蛋白(OCT) 1-3和多药和有毒化合物挤压(MATE) 1-2的表达影响。在细胞内，二甲双胍抑制线粒体功能，从而导致耗氧量降低和增殖抑制。减少氧气消耗可以改善肿瘤的氧合和辐射反应。目的:在这里，我们试图确定二甲双胍在抑制耗氧、增殖和OCTs和MATEs表达方面的影响是否与19个癌细胞系之间存在关联。结果:不同细胞系对二甲双胍的抗增殖反应存在相对较大的变异性，其中一部分细胞系非常耐药。相比之下，所有细胞系都表现出对二甲双胍抑制氧消耗的敏感性，变化相对较小。OCT1的表达与OCT2、OCT3的表达相关。OCT1和OCT2表达相对均匀，而OCT3、MATE1和MATE2表达在系间差异较大。对增殖抑制的抵抗与MATE2表达之间，以及对耗氧抑制的敏感性与OCT3表达之间，存在统计学意义上的相关性。 One cell line (LNCaP) with high OCT3 and low MATE2 expression in concert, had substantially higher intracellular metformin concentration than other cell lines, and was exquisitely sensitive to both anti-proliferative and anti-respiratory effects. In all other cell lines, the concentration of metformin required to inhibit oxygen consumption acutely in vitro was substantially higher than that achieved in the plasma of diabetic patients. However, administering anti-diabetic doses of metformin to tumor-bearing mice resulted in intratumoral accumulation of metformin and reduced hypoxic tumor fractions. CONCLUSIONS: All cancer cells are susceptible to inhibition of oxygen consumption by metformin, which results in reduced hypoxic tumor fractions beneficial for the response to radiotherapy. High MATE2 expression may result in resistance to the anti-proliferative effect of metformin and should be considered as a negative predictive biomarker in clinical trials.

引用本文的药物库数据

药物转运蛋白

药物	转运体	种类	生物	药理作用	行动
二甲双胍	多药和毒素挤压蛋白2	蛋白质	人类	未知的	底物	细节