Molecular Pathways: Regulation and Therapeutic Implications of Multidrug Resistance

被引:156
作者
Chen, Kevin G. [1 ,2 ]
Sikic, Branimir I. [1 ]
机构
[1] Stanford Univ, Dept Med, Div Oncol, Sch Med, Stanford, CA 94305 USA
[2] Natl Inst Neurol Disorders & Stroke, NIH Stem Cell Unit, NIH, Bethesda, MD USA
关键词
ACUTE MYELOID-LEUKEMIA; PHASE-I TRIAL; HUMAN MDR1 GENE; P-GLYCOPROTEIN EXPRESSION; BREAST-CANCER CELLS; TRANSCRIPTIONAL REGULATION; LYMPHOCYTIC-LEUKEMIA; EPIGENETIC CHANGES; DRUG-RESISTANCE; PROMOTER REGION;
D O I
10.1158/1078-0432.CCR-11-1590
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Multidrug transporters constitute major mechanisms of MDR in human cancers. The ABCB1 (MDR1) gene encodes a well-characterized transmembrane transporter, termed P-glycoprotein (P-gp), which is expressed in many normal human tissues and cancers. P-gp plays a major role in the distribution and excretion of drugs and is involved in intrinsic and acquired drug resistance of cancers. The regulation of ABCB1 expression is complex and has not been well studied in a clinical setting. In this review, we elucidate molecular signaling and epigenetic interactions that govern ABCB1 expression and the development of MDR in cancer. We focus on acquired expression of ABCB1 that is associated with genomic instability of cancer cells, including mutational events that alter chromatin structures, gene rearrangements, and mutations in tumor suppressor proteins (e. g., mutant p53), which guard the integrity of genome. In addition, epigenetic modifications of the ABCB1 proximal and far upstream promoters by either demethylation of DNA or acetylation of histone H3 play a pivotal role in inducing ABCB1 expression. We describe a molecular network that coordinates genetic and epigenetic events leading to the activation of ABCB1. These mechanistic insights provide additional translational targets and potential strategies to deal with clinical MDR. Clin Cancer Res; 18(7); 1863-9. (C) 2012 AACR.
引用
收藏
页码:1863 / 1869
页数:7
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