Kuo Macus Tien
Department of Molecular Pathology (Unit 951), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Antioxid Redox Signal. 2009 Jan;11(1):99-133. doi: 10.1089/ars.2008.2095.
The development of multidrug resistance to cancer chemotherapy is a major obstacle to the effective treatment of human malignancies. It has been established that membrane proteins, notably multidrug resistance (MDR), multidrug resistance protein (MRP), and breast cancer resistance protein (BCRP) of the ATP binding cassette (ABC) transporter family encoding efflux pumps, play important roles in the development of multidrug resistance. Overexpression of these transporters has been observed frequently in many types of human malignancies and correlated with poor responses to chemotherapeutic agents. Evidence has accumulated showing that redox signals are activated in response to drug treatments that affect the expression and activity of these transporters by multiple mechanisms, including (a) conformational changes in the transporters, (b) regulation of the biosynthesis cofactors required for the transporter's function, (c) regulation of the expression of transporters at transcriptional, posttranscriptional, and epigenetic levels, and (d) amplification of the copy number of genes encoding these transporters. This review describes various specific factors and their relevant signaling pathways that are involved in the regulation. Finally, the roles of redox signaling in the maintenance and evolution of cancer stem cells and their implications in the development of intrinsic and acquired multidrug resistance in cancer chemotherapy are discussed.
癌症化疗多药耐药性的发展是有效治疗人类恶性肿瘤的主要障碍。已经确定，膜蛋白，尤其是ATP结合盒（ABC）转运蛋白家族中编码外排泵的多药耐药（MDR）、多药耐药相关蛋白（MRP）和乳腺癌耐药蛋白（BCRP），在多药耐药性的发展中起重要作用。在许多类型的人类恶性肿瘤中经常观察到这些转运蛋白的过表达，并且与对化疗药物的不良反应相关。越来越多的证据表明，氧化还原信号在药物治疗的响应中被激活，通过多种机制影响这些转运蛋白的表达和活性，包括：（a）转运蛋白的构象变化；（b）转运蛋白功能所需生物合成辅因子的调节；（c）在转录、转录后和表观遗传水平上对转运蛋白表达的调节；（d）编码这些转运蛋白的基因拷贝数的扩增。本综述描述了参与调节的各种特定因素及其相关信号通路。最后，讨论了氧化还原信号在癌症干细胞的维持和演变中的作用及其在癌症化疗中内在和获得性多药耐药性发展中的意义。
