Overcoming drug resistance by regulating nuclear receptors

被引:78
作者
Chen, Taosheng [1 ]
机构
[1] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA
基金
美国国家卫生研究院;
关键词
Drug resistance; MDR1; PXR; CYP3A4; ABC transporters; Drug-metabolizing enzymes; PREGNANE-X-RECEPTOR; ACUTE MYELOID-LEUKEMIA; BLOOD-BRAIN-BARRIER; CONSTITUTIVE ANDROSTANE RECEPTOR; INTESTINAL P-GLYCOPROTEIN; CYP3A4; GENE-EXPRESSION; MULTIDRUG-RESISTANCE; XENOBIOTIC RECEPTOR; BREAST-CANCER; CYTOCHROME-P450; 3A;
D O I
10.1016/j.addr.2010.07.008
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Drug resistance involves multiple mechanisms. Multidrug resistance (MDR) is the leading cause of treatment failure in cancer therapy. Elevated levels of MDR proteins [members of the ATP-binding cassette (ABC) transporter family] increase cellular efflux and decrease the effectiveness of chemotherapeutic agents. As a salvage approach to overcome drug resistance, inhibitors of MDR proteins have been developed, but have had limited success mainly due to undesired toxicities. Nuclear receptors (NRs), including pregnane X receptor (PXR), regulate the expression of proteins (including MDR proteins) involved in drug metabolism and drug clearance, suggesting that it is possible to overcome drug resistance by regulating NR. This review discusses the progress in the development of MDR inhibitors, with a focus on MDR1 inhibitors. Recent development of PXR antagonists to pharmacologically modulate PXR is also reviewed. The review proposes that selectively preventing the elevation of MDR levels by regulating NRs 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. (C) 2010 Elsevier B.V. All rights reserved.
引用
收藏
页码:1257 / 1264
页数:8
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