MATE2表达与癌细胞对二甲双胍的回应。

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Chowdhury年代,荣智健E, Pintilie M, Muaddi H,沙伊布,Yeung M, Fusciello M,赛克斯J,投手B, Hagenkort,麦基T, Vellanki R,陈E,布里斯托RG,武泰BG, Koritzinsky M

MATE2表达与癌细胞对二甲双胍的回应。

《公共科学图书馆•综合》。2016年12月13日,11 (12):e0165214。doi: 10.1371 / journal.pone.0165214。eCollection 2016。

PubMed ID

27959931 (在PubMed

]

文摘

背景:有极大的兴趣在再利用常用抗糖尿病药物二甲双胍对癌症治疗。二甲双胍的细胞内吸收和保留是影响有机阳离子转运蛋白的表达(10月)1 - 3和多种药物和有毒化合物挤压(配偶)1 - 2。细胞内,二甲双胍抑制线粒体功能,导致减少耗氧量和抑制增殖。减少耗氧量会导致肿瘤改善氧化和辐射响应。目的:我们试图确定有一个关联的影响二甲双胍抑制氧消耗,扩散和表达10月和配偶的19个小组癌症细胞系。结果:有相对较大的可变性anti-proliferative响应不同的细胞系,二甲双胍与细胞系非常耐药的一个子集。相比之下,所有的细胞系表现出对二甲双胍抑制耗氧量,与相对较小的变化。的表达OCT2和OCT3 OCT1与表达式。OCT1 OCT2相对统一表达,而表达OCT3、MATE1和跨线MATE2呈现明显差异。有显著抑制扩散阻力和MATE2表达之间的联系,以及抑制敏感性之间的耗氧量和OCT3表达式。 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.

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药物转运蛋白

药物	转运体	类	生物	药理作用	行动
二甲双胍	多种药物和毒素挤压蛋白2	蛋白质	人类	未知的	底物	细节