Laboratory of Clinical Pharmacology, Department of Hematology, Xiang-Ya Hospital, Central-South University, Changsha 410008, People's Republic of China.
Med Hypotheses. 2010 Jan;74(1):92-4. doi: 10.1016/j.mehy.2009.07.036. Epub 2009 Aug 22.
It is well known that the mechanism of action of chemotherapeutic drugs and their ability to induce multidrug resistance (MDR) are of relevance to cancer treatment. Although MDR is a multifactorial process, the main obstacle is the expression of multidrug-efflux pumps that lowers the intracellular drug levels. P-glycoprotein (P-gp) is the longest identified efflux pump. Thus, P-gp has been looked as a well established mediator of MDR and it became a therapeutic target for circumventing multidrug resistance. However, the mechanism of adjusting the expression of P-gp is not clear yet. The results of the effect of genetic polymorphism on P-gp expression and function remain conflicting. More recently, studies on the regulation of MDR1 has widened to examine the role of epigenetics and some new results were found to support the effect of epigenetic variance in vitro. It is hence hypothesized that epigenetic variants play more important roles than genetic polymorphism, thus adjusting the epigenetic factors could alter the expression of MDR, leading to the reverse of MDR. And it is further hypothesized that histone deacetylase inhibitors could be another strategy to overcome MDR. The mechanism may include a bidirectional modulation of P-gp by histone deacetylase inhibitors.
众所周知，化疗药物的作用机制及其诱导多药耐药（MDR）的能力与癌症治疗有关。尽管 MDR 是一个多因素的过程，但主要障碍是多药外排泵的表达降低了细胞内药物水平。P-糖蛋白（P-gp）是鉴定出的最长的外排泵。因此，P-gp 被视为 MDR 的一个成熟的介导物，并且成为规避多药耐药的治疗靶点。然而，调节 P-gp 表达的机制尚不清楚。遗传多态性对 P-gp 表达和功能的影响的结果仍然存在冲突。最近，对 MDR1 调节的研究已经扩大到研究表观遗传学的作用，并发现了一些新的结果支持体外表观遗传变异的作用。因此，假设表观遗传变异比遗传多态性发挥更重要的作用，因此调节表观遗传因素可以改变 MDR 的表达，导致 MDR 的逆转。进一步假设组蛋白去乙酰化酶抑制剂可能是克服 MDR 的另一种策略。其机制可能包括组蛋白去乙酰化酶抑制剂对 P-gp 的双向调节。
