Minor role of pregnane-x-receptor for acquired multidrug resistance in head and neck squamous cell carcinoma in vitro
| Autor: | Dirk Theile, Juan Pablo Rigalli, Christel Herold-Mende, Gerhard Dyckhoff, Walter E. Haefeli, Johanna Weiss, Tasmin Reuter |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Receptors
Steroid Cancer Research Farmacología y Farmacia CIENCIAS MÉDICAS Y DE LA SALUD Paclitaxel PXR Blotting Western Antineoplastic Agents Biology Real-Time Polymerase Chain Reaction Toxicology digestive system HNSCC Inhibitory Concentration 50 chemistry.chemical_compound Cell Line Tumor MDR medicine Humans Pharmacology (medical) Pharmacology Cisplatin Pregnane X receptor Gene knockdown CYP3A4 Pregnane X Receptor CHEMOTHERAPY medicine.disease Head and neck squamous-cell carcinoma Drug Resistance Multiple digestive system diseases Gene Expression Regulation Neoplastic Multiple drug resistance Medicina Básica Real-time polymerase chain reaction Oncology chemistry Drug Resistance Neoplasm Head and Neck Neoplasms Gene Knockdown Techniques Immunology Carcinoma Squamous Cell Cancer research Fluorouracil Rifampin medicine.drug |
| Popis: | 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. Fil: Rigalli, Juan Pablo. University of Heidelberg. Department of Clinical Pharmacology and Pharmacoepidemiology; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina Fil: Reuter, Tasmin . University of Heidelberg. Department of Clinical Pharmacology and Pharmacoepidemiology; Alemania Fil: Herold Mende, Christel. University of Heidelberg; Alemania Fil: Dyckhoff, Gerhard. University of Heidelberg; Alemania Fil: Haefeli, Walter Emil. University of Heidelberg. Department of Clinical Pharmacology and Pharmacoepidemiology; Alemania Fil: Weiss, Johanna. University of Heidelberg. Department of Clinical Pharmacology and Pharmacoepidemiology; Alemania Fil: Theile, Dirk. University of Heidelberg. Department of Clinical Pharmacology and Pharmacoepidemiology; Alemania |
| Databáze: | OpenAIRE |
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