Nuclear receptor-mediated induction of drug metabolizing enzymes and transporters by anticancer drugs

Abstract

Role of nuclear receptors in adverse anticancer drug reactions? Unwanted drug-drug interactions and the development of multidrug resistance are ongoing concerns in the treatment of cancer patients. A common factor that is shared by both phenomena is enzyme induction. Especially, the induction of enzymes involved in the metabolism and disposition of anticancer drugs can pose a major health risk. Since anticancer drugs have a very narrow therapeutic window, small alterations in the pharmacokinetic profile of these agents can have far reaching clinical consequences. Indeed, several well-known enzyme inducers such as the antibiotic rifampicin, the anticonvulsants phenobarbital and phenytoin, and the over-the-counter herbal antidepressant St.John’swort, have been shown to cause intoxications or loss of therapeutic efficacy when combined with anticancer drugs. These drugs were shown to mediate enzyme induction by activating the pregnane X receptor (PXR): a very promiscuous nuclear receptor involved in the regulation of cytochrome P450 3A4 and P-glycoprotein. Interestingly, we show that established anticancer drugs such as paclitaxel, tamoxifen, oxazophosphorines, but also the novel and very promising tyrosine kinase inhibitors erlotinib, gefitinib and nilotinib are activators of PXR as well. Upon activation by these anticancer drugs, PXR mediates the induction of CYP3A4 and Pgp and enhances the biotransformation of CYP3A4 substrates. Additionally, reduced cellular accumulation of Pgp substrates was observed. These results indicate that PXR plays an important role in pharmacokinetic (anticancer) drug-anticancer drug interactions. Furthermore, since induction of drug transporters, and to a lesser extent induction of drug metabolizing enzymes, is one of the main mechanisms by which cancer cells acquire resistance against multiple agents, the role of PXR activation in multidrug resistance was evaluated. Activation of PXR, and subsequent Pgp induction by tumor cells, results in reduced cellular accumulation of anticancer agents and renders these tumor cells resistant to anticancer drugs. Together, these results show that PXR is an important mediator of unwanted drug-drug interactions and plays a role in the development of multidrug resistance.