Overcoming drug resistance by regulating nuclear receptors.
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.
Chen
Taosheng
T
Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. Taosheng.Chen@STJUDE.ORG
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid