孕烷X受体与肿瘤多药耐药

Pregnane X receptor and multidrug resistance

多药耐药(MDR)是肿瘤化疗失败的主要原因之一。MDR的产生主要由ATP结合盒(ABC)转运蛋白超家族的跨膜蛋白所引起,其中P-糖蛋白及其编码基因mdr1的过表达是MDR产生的最主要机制。研究MDR的产生机制,寻找诱发mdr1表达的诱因并阻断其表达,是克服肿瘤多药耐药性行之有效的方法。近来研究发现,孕烷X受体(PXR)可介导mdr1的表达,活化的PXR诱导MDR1的表达。因此,特异性地阻断PXR的活化可抑制mdr1的表达,从而克服多药耐药性。现已发现多种物质可作为PXR抑制剂或拮抗剂。本文即对核受体PXR与MDR、PXR抑制剂及拮抗剂的研究现状做一介绍,以期为克服肿瘤多药耐药提供参考。

Multidrug resistance（MDR） is the leading cause of treatment failure in cancer therapy. Overexpression of the ATP-binding cassette（ABC） transporter family increases the cellular efflux, decreases the effectiveness of chemotherapeutic agents,and results in MDR. In particular,overexpression of P-glycoprotein and its encoding genes（mdr1） is the major mechanism. It is feasible for overcoming MDR by studying the factors affecting mdr1 gene expression so as to block the expression of mdr1. Pregnane X receptor（PXR） can regulate the expression of MDR proteins,suggesting that it be possible to overcome drug resistance by regulating PXR. In this paper,the relation between PXR and MDR and recent development of PXR antagonists to pharmacologically modulate PXR are reviewed. The review proposes that selectively preventing the elevation of MDR levels by regulating PXR rather than non-selectively inhibiting the MDR activity by using MDR inhibitors can be a less toxic approach to overcome drug resistance during cancer therapy.