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

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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.

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Acknowledgments

Parts of the project were funded by Grants #107173 and #107204 from the German Cancer Aid. Juan Pablo Rigalli was supported by a grant from the German Academic Exchange Service. The authors thank Corina Mueller for excellent technical assistance.

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Juan Pablo Rigalli, Tasmin Reuter, Walter Emil Haefeli, Johanna Weiss & Dirk Theile

  2. Institute of Experimental Physiology (CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Suipacha 570, 2000, Rosario, Argentina

    Juan Pablo Rigalli

  3. Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany

    Christel Herold-Mende

  4. Section of Molecular Cell Biology Group, Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany

    Christel Herold-Mende & Gerhard Dyckhoff

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  1. Juan Pablo Rigalli
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  2. Tasmin Reuter
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  3. Christel Herold-Mende
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Correspondence to Johanna Weiss.

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Rigalli, J.P., Reuter, T., Herold-Mende, C. et al. Minor role of pregnane-x-receptor for acquired multidrug resistance in head and neck squamous cell carcinoma in vitro. Cancer Chemother Pharmacol 71, 1335–1343 (2013). https://doi.org/10.1007/s00280-013-2133-x

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  • DOI: https://doi.org/10.1007/s00280-013-2133-x

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