摘要
永久性选择癌细胞进行存活和增殖。在此过程中,肿瘤细胞通常会选择基本的生理机制来保护自己免受有毒化疗。这些机制之一是ATP结合盒(ABC)药物外排泵的过表达,通过增加药物流出导致癌细胞的多药耐药(MDR)。在过去20年中,通过抑制ABC转运蛋白,已经做出了许多努力来规避MDR。发现了这些转运蛋白的一些抑制剂,但很少具体或合理开发。除了这种方法外,近来出现了一种新的治疗耐药性肿瘤细胞治疗策略,即观察到表达高水平的这些泵的癌细胞出现意想不到的超敏反应,称为选择的化合物亚组的抵抗敏感性(CS)。在本综述中,我们针对多药耐药蛋白1(MRP1),并且在非全面突出MRP1的一些最典型的抑制剂及其表达调节剂之后,我们专注于特异性靶向MRP1的CS试剂,当MRP1过表达时,多药耐药性癌细胞所谓的“跟腱”。我们讨论了谷胱甘肽易位的突出作用和细胞的相关氧化还原平衡与某些类型化合物诱导的CS之间的联系。后者根据其化学分类进行了讨论,提出了成功根除耐药性癌症的发展前景。
关键词: ABCC1 / MRP1,多药耐药蛋白1,谷胱甘肽,侧枝敏感性,药物设计,类黄酮,分子模型,多药耐药性,定量结构 - 活性关系
Current Medicinal Chemistry
Title:MRP1-dependent Collateral Sensitivity of Multidrug-resistant Cancer Cells: Identifying Selective Modulators Inducing Cellular Glutathione Depletion
Volume: 24 Issue: 12
关键词: ABCC1 / MRP1,多药耐药蛋白1,谷胱甘肽,侧枝敏感性,药物设计,类黄酮,分子模型,多药耐药性,定量结构 - 活性关系
摘要: Cancer cells are permanently being selected for survival and proliferation. During this process, tumor cells often co-opt basic physiological mechanisms to protect themselves from toxic chemotherapy. One of these mechanisms is the overexpression of ATP-binding cassette (ABC) drug efflux pumps leading to multidrug resistance (MDR) of cancer cells through an increase of drug efflux. In the past 20 years, many efforts were done to circumvent MDR through the inhibition of ABC transporters. A number of inhibitors of these transporters were found but are rarely specific or rationally developed. Beside this approach, a new therapeutic strategy towards eradicating drug resistant tumor cells has recently emerged from the observation that cancer cells expressing a high level of these pumps show an unexpected hypersensitivity, called collateral sensitivity (CS) to a selected subset of chemical compounds. In this review, we target the multidrug resistance protein 1 (MRP1) and after a non-exhaustively highlighting of some of the most exemplary inhibitors of MRP1 and modulators of its expression, we focus on CS agents specifically targeting MRP1 which becomes, when overexpressed, the so called "Achilles' heel" of multidrug resistant cancer cells. We discuss the link between the prominent role of glutathione translocation and related redox balance of the cell and the CS induced by certain types of compounds. The latter are discussed according to their chemical class, and perspectives in their development for successful eradication of resistant cancer are proposed.
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MRP1-dependent Collateral Sensitivity of Multidrug-resistant Cancer Cells: Identifying Selective Modulators Inducing Cellular Glutathione Depletion, Current Medicinal Chemistry 2017; 24 (12) . https://dx.doi.org/10.2174/0929867324666161118130238
DOI https://dx.doi.org/10.2174/0929867324666161118130238 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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