Drug resistance and cellular adaptation to tumor acidic pH microenvironment.
Drug resistance and cellular adaptation to tumor acidic pH microenvironment.
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DOI：
10.1021/mp200292c
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发表时间：
2011-12-05
影响因子：
4.9
通讯作者：
Gillies RJ
中科院分区：
文献类型：
--
作者：
Wojtkowiak JW;Verduzco D;Schramm KJ;Gillies RJ
尽管在开发新的治疗策略方面取得了进展，但癌症相关死亡的主要因素仍然是对治疗的抵抗。除了由异生素转运蛋白或结合位点突变介导的生化抗性之外，抗性可以是生理性的;作为肿瘤的物理微环境的结果而出现。这篇综述的重点是细胞外酸中毒，最终结果高糖酵解通量和不良的血管灌注。低细胞外pH（pHe）形成由“离子捕获”现象描述的生理药物屏障。我们描述了酸外质膜pH梯度如何对弱碱性化疗的药物疗效产生负面影响，但更适合于弱酸性治疗。我们还将探讨肿瘤细胞对细胞外酸中毒的生理变化，这些变化有助于耐药，包括凋亡潜力降低、遗传改变和多药转运蛋白（p-糖蛋白，pGP）活性升高。由于低pH是实体瘤的标志，因此可以开发旨在克服或利用这种状况的治疗策略。
Despite advances in developing novel therapeutic strategies, a major factor underlying cancer related death remains resistance to therapy. In addition to biochemical resistance, mediated by xenobiotic transporters or binding site mutations, resistance can be physiological; emerging as a consequence of the tumor’s physical microenvironment. This review focuses on extracellular acidosis, an end result of high glycolytic flux and poor vascular perfusion. Low extracellular pH, pHe, forms a physiological drug barrier described by an “ion trapping” phenomenon. We describe how the acid-outside plasmalemmal pH gradient negatively impacts drug efficacy of weak base chemotherapies but is better suited for weakly acidic therapeutics. We will also explore the physiologic changes tumor cells undergo in response to extracellular acidosis which contribute to drug resistance including reduced apoptotic potential, genetic alterations, and elevated activity of a multidrug transporter, p-glycoprotein, pGP. Since low pHe is a hallmark of solid tumors, therapeutic strategies designed to overcome or exploit this condition can be developed.
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影响因子：
3.1
作者：
Hoekstra, H. J.
通讯作者：
Hoekstra, H. J.
影响因子：
2.9
作者：
Hashim, Arig Ibrahim;Zhang, Xiaomeng;Wojtkowiak, Jonathan W.;Martinez, Gary V.;Gillies, Robert J.
通讯作者：
Gillies, Robert J.
影响因子：
2.6
作者：
BROWN, JM
通讯作者：
BROWN, JM
影响因子：
2.9
作者：
GOOD, NE;WINGET, GD;SINGH, RMM
通讯作者：
SINGH, RMM
影响因子：
4.5
作者：
Chen JL;Lucas JE;Schroeder T;Mori S;Wu J;Nevins J;Dewhirst M;West M;Chi JT
通讯作者：
Chi JT