Role of the Pregnane X Receptor in the Clinical Resistance to all‐trans Retinoic Acid

Abstract

All-trans-retinoic acid (ATRA) is effective for treatment of acute promyelocytic leukemia and several solid tumors. But resistance to ATRA develops rapidly due to increased metabolism. The most studied mechanism is its auto-induced metabolism regulated by the RAR – CYP26 pathway. However, treatment of cancer is usually not done with a single antineoplastic agent, but with a variety of combined chemotherapy regimens, as well as concomitant administration of other supportive drugs. The pregnane X receptor (PXR) is the most important xenobiotic sensor. Many prescription drugs are PXR ligands and, PXR target genes, phase I, phase II enzymes, and drug transporters, are largely involved in metabolizing and excreting xenobiotics. Thus, we hypothesize that the existence of potential PXR ligands in concomitant drugs might increase ATRA metabolism and cause its resistance through activation of the PXR – PXR-target-gene pathway. Because of species differences in response to PXR ligands, we used Pxr-null, wild-type and PXR-humanized transgenic mouse models. The clinically relevant PXR ligands (rifampicin, nifedipine, lovastatin, dexamethasone) all increased ATRA metabolism both in vitro and in vivo, which was PXR dependant, and the up-regulation of CYP3A was the major contributor. This study revealed that coadministration of PXR ligands might lead to ATRA resistance through activation of the PXR – CYP3A pathway.