Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 5, pp 1335–1343

Minor role of pregnane-x-receptor for acquired multidrug resistance in head and neck squamous cell carcinoma in vitro

  • Juan Pablo Rigalli
  • Tasmin Reuter
  • Christel Herold-Mende
  • Gerhard Dyckhoff
  • Walter Emil Haefeli
  • Johanna Weiss
  • Dirk Theile
Original Article

DOI: 10.1007/s00280-013-2133-x

Cite this article as:
Rigalli, J.P., Reuter, T., Herold-Mende, C. et al. Cancer Chemother Pharmacol (2013) 71: 1335. doi:10.1007/s00280-013-2133-x

Abstract

Purpose

Acquired multidrug resistance (MDR) has been linked to overexpression of drug-metabolising and transporting proteins mediated by pregnane-x-receptor (PXR). The aim of this work was to establish the relevance of PXR for MDR in head and neck squamous cell carcinoma (HNSCC).

Methods

Using eight HNSCC cell lines, we determined the efficacy of paclitaxel, cisplatin and 5-fluorouracil (5-FU) via proliferation assays and determined the expression and activity of PXR through quantitative real-time polymerase chain reaction, western blotting and luciferase-based reporter gene assay. PXR knockdown approaches using shRNA-encoding vectors were applied to estimate the role of PXR for native MDR.

Results

Drug resistance ranged between 5.2 and 620 nM for paclitaxel, varied between 4.5 and 58 μM for cisplatin, and varied between 1.1 and 5,467 μM for 5-FU. Lack of PXR mRNA expression was mostly accompanied by the absence of mRNA expression of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp, ABCB1) expression. Neither mRNA nor protein expression of PXR correlated with drug resistance. However, PXR activity tended to correlate with IC50 values of paclitaxel (p = 0.08). Knockdown of PXR in one of the cell lines had a slight but not significant impact on paclitaxel efficacy compared to scrambled sequence control. Surprisingly, only in two cell lines, PXR activity was increased by the well-known inductor rifampicin.

Conclusion

This study suggests a malfunctioning of PXR and thus a minor relevance for iatrogenic chemotherapy resistance in HNSCC.

Keywords

CytostaticsHead and neck squamous cell carcinomaMultidrug resistancePregnane-x-receptor

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Juan Pablo Rigalli
    • 1
    • 2
  • Tasmin Reuter
    • 1
  • Christel Herold-Mende
    • 3
    • 4
  • Gerhard Dyckhoff
    • 4
  • Walter Emil Haefeli
    • 1
  • Johanna Weiss
    • 1
  • Dirk Theile
    • 1
  1. 1.Department of Clinical Pharmacology and PharmacoepidemiologyUniversity of HeidelbergHeidelbergGermany
  2. 2.Institute of Experimental Physiology (CONICET), Faculty of Biochemical and Pharmaceutical ScienceRosario National UniversityRosarioArgentina
  3. 3.Division of Neurosurgical Research, Department of NeurosurgeryUniversity of HeidelbergHeidelbergGermany
  4. 4.Section of Molecular Cell Biology Group, Department of Otorhinolaryngology, Head and Neck SurgeryUniversity of HeidelbergHeidelbergGermany