The role of pregnane X receptor (PXR) in cancer drug resistance and identification of novel PXR antagonists

Abstract

Pregnane X receptor (PXR) is a ligand-activated transcription factor that regulates genes encoding xenobiotic metabolizing enzymes and transporters. In cancer cells, PXR activation appears to enhance cancer drug resistance. Therefore, PXR antagonism has been suggested as a potential approach in cancer therapy. The aims of this work were to verify the putative role of PXR in cancer drug resistance and to identify novel PXR antagonists. Several cancer drug resistance-associated genes were differently expressed in cisplatin- and irinotecan-resistant colorectal cancer LS174T cells compared to parental cells. In cisplatin-resistant cells, none of the relevant genes associated with cisplatin resistance were affected by PXR modulation; therefore, PXR appears not to play a role in cisplatin resistance. On the contrary, in irinotecan-resistant cells specific resistance-associated genes were affected by PXR activation and inhibition. Irinotecan-resistant cells exhibited also cross-resistance towards paclitaxel and this cross-resistance was reduced by PXR antagonism. These results suggest that PXR antagonism is a potential approach to attenuate drug resistance in cancer cells, if the resistance is for the most part dependent on PXR-regulated genes. The Tübingen Kinase Inhibitor Collection compound library was investigated to identify novel PXR antagonists. Four novel potential PXR antagonists and one potential full agonist were identified. These novel antagonists appeared to be passive, competitive antagonists with partial agonist activity. They also demonstrated direct binding to PXR and impaired the rifampicin-induced coactivator interactions with PXR. Moreover, these antagonists elicited gene-specific effects on endogenous PXR target gene expression and displayed selectivity towards PXR among the NR1I group of nuclear receptors. Interestingly, subtle changes in the functional groups of these compounds altered considerably the PXR activation and inhibition potential.