Expression, activity, and inducibility of pregnane-x-receptor and its role in multidrug-resistance in head and neck squamous cell carcinoma.

RIGALLI JP; HEROLD-MENDE C; DYCKHOFF G; HAEFELI WE; WEISS J; THEILE D

Congreso; SAO PAULO SCHOOL OF ADVANCED SCIENCE. Advances in Molecular Oncology; 2013

FAPESP - Faculdade de Medicina of the University of São Paulo

Acquired multidrug resistance (MDR) has been linked to overexpression of drugmetabolising and transporting proteins mediated by pregnane xenobiotic receptor (PXR).Relevance of PXR for MDR in head and neck squamous cell carcinoma (HNSCC) isunknown.Using eight HNSCC cell lines we determined efficacy of paclitaxel, cisplatin, and 5-fluorouracil (5-FU) via crystal violet staining and determined expression and activity ofPXR through quantitative real-time polymerase chain reaction (qRT-PCR), westernblotting, and luciferase-based reporter-gene-assay. PXR knock-down approaches usingshRNA encoding vectors were applied to scrutinise role of PXR for (acquired) MDR.Drug resistance ranged between 5.20 nM to 620.75 nM for paclitaxel, varied between 4.49μM and 58.74 for cisplatin, and varied between 1.08 μM and 5467.5 for 5-FU. Lack of PXRmRNA expression was mostly accompanied by absence of CYP3A4 and ABCB1 mRNAexpression. In contrast to mRNA or protein expression, PXR activity did positively correlatewith IC50 values of paclitaxel and 5-FU, respectively. However, only in two cell lines PXRactivity was weakly increased by well-known inducer rifampicin. Knock-down of PXR had aslight but not significant impact on paclitaxel efficacy compared to scrambled sequencecontrol (paclitaxel IC50 decrease from 5.7 nM to 4.0 nM).PXR is suggested to play an important role for per se cytostatic efficacy in HNSCC, but tobe less responsible for acquired MDR. This may result rather resulting from clonalselection of intrinsically resistant cells than from increased transcription of drugmetabolising or transporting proteins mediated by nuclear receptors such as PXR.