摘要
Overexpression of P-glycoprotein （P-gp） encoded by the multidrug resistance gene-1 （MDR-1） is the main mechanism responsible for multidrug resistance （MDR） in a majority of cancer cells. However, the mechanism by which cancer cells acquire high levels of P-gp has not been well defined. Accumulating evidence suggests that nuclear receptors （NRs）, especially human pregnane X receptor （PXR）, play a crucial role in multidrug resistance. It has been shown that chemotherapeutic drug activates PXR and then enhances P-gp expression. Genetic knockdown or pharmacologic inhibition of PXR led to attenuation of drug-induced MDR1 over expression, implying that NRs may be an effective target to reverse multidrug resistance. Recent investigations suggested that transcriptional activity of NRs is mediated by methylases, the important enzymes involved in epigenetic regulation. Other epigenetic modifications, such as promoter methylation, histone deacetylases and microRNAs, were also found to be involved in activation of MDR1 promoter, though the underlying mechanisms are not thoroughly known. In this review, we summarized recent researches in the regulation of P-gp expression, with particular focus on NRs and epigenetics, aiming to provide references and options to reverse and/or prevent MDR in cancer treatment.
由多药耐药基因1(multidrug resistance gene-1,MDR-1)编码的P-糖蛋白(P-glycoprotein,P-gp)的过表达是肿瘤细胞产生多药耐药的主要机制。然而,肿瘤细胞通过何种途径获得高水平的P-gp尚不完全清楚。越来越多的研究显示核受体,尤其是孕烷X受体(pregnane X receptor,PXR),在其中发挥了作用。大量研究显示化疗药物通过激活PXR而增强Pgp的表达。基因敲除或药物抑制PXR削弱药物诱导的MDR1过表达,这提示核受体可能成为逆转多药耐药的一个有效靶点。近期,有研究显示核受体的转录调控活性受表观遗传修饰中一类重要酶甲基化酶的影响。与此同时,尽管机制尚不完全清楚,其他的表观遗传修饰如启动子甲基化、组蛋白去乙酰化以及microR NAs调控等也被发现参与MDR1启动子的活化。在这篇综述中,我们概述了P-gp表达调控相关的近期研究,尤其是核受体和表观遗传学调控,希望为逆转或预防肿瘤治疗中的多药耐药提供参考和选择。
