Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters

Abstract

Chemotherapy is one of the three most common treatment modalities for cancer. However, its efficacy is limited by multidrug resistant cancer cells. Drug metabolizing enzymes (DMEs) and efflux transporters promote the metabolism, elimination, and detoxification of chemotherapeutic agents. Consequently, elevated levels of DMEs and efflux transporters reduce the therapeutic effectiveness of chemotherapeutics and, often, lead to treatment failure. Nuclear receptors, especially pregnane X receptor (PXR, NR1I2) and constitutive androstane activated receptor (CAR, NR1I3), are increasingly recognized for their role in xenobiotic metabolism and clearance as well as their role in the development of multidrug resistance (MDR) during chemotherapy. Promiscuous xenobiotic receptors, including PXR and CAR, govern the inducible expressions of a broad spectrum of target genes that encode phase I DMEs, phase II DMEs, and efflux transporters. Recent studies conducted by a number of groups, including ours, have revealed that PXR and CAR play pivotal roles in the development of MDR in various human carcinomas, including prostate, colon, ovarian, and esophageal squamous cell carcinomas. Accordingly, PXR/CAR expression levels and/or activation statuses may predict prognosis and identify the risk of drug resistance in patients subjected to chemotherapy. Further, PXR/CAR antagonists, when used in combination with existing chemotherapeutics that activate PXR/CAR, are feasible and promising options that could be utilized to overcome or, at least, attenuate MDR in cancer cells.

Figure 1

Regulation of Phase I & II DMEs and drug transporter genes by nuclear receptors PXR and CAR. After ligand binding, cytoplasimc fractions of PXR translocates to the nucleus while CAR dissociates from its complex, comprised of tetratricopeptide repeat (TTR), cytoplasmic CAR retention protein (CCRP), 90-kDa heat shock protein (hsp90) and PPP1R16A, and translocates from the cytoplasm to the nucleus. Subsequently, both PXR and CAR form heterodimers with RXR and bind to their respective response elements to stimulate transcription of phase I & II DMEs and drug transporters.