Inhibition of P-glycoprotein functionality by vandetanib may reverse cancer cell resistance to doxorubicin
| Autor: | J. Bénard, Sophie Gil, Robert Farinotti, F. Forestier, J.M. Bidart, Cécile Jovelet |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
ATP Binding Cassette Transporter
Subfamily B Time Factors Cell Survival medicine.drug_class Pharmaceutical Science Pharmacology Vandetanib Tyrosine-kinase inhibitor Piperidines Cell Line Tumor medicine ATP Binding Cassette Transporter Subfamily G Member 2 Humans Rhodamine 123 Doxorubicin ATP Binding Cassette Transporter Subfamily B Member 1 Protein Kinase Inhibitors Cell Proliferation Fluorescent Dyes P-glycoprotein Ovarian Neoplasms Antibiotics Antineoplastic Dose-Response Relationship Drug biology Fluoresceins Neoplasm Proteins Multiple drug resistance Phenotype Drug Resistance Neoplasm Cell culture Cancer cell Quinazolines biology.protein ATP-Binding Cassette Transporters Female Efflux Cisplatin Multidrug Resistance-Associated Proteins medicine.drug |
| Zdroj: | European Journal of Pharmaceutical Sciences. 46:484-491 |
| ISSN: | 0928-0987 |
| DOI: | 10.1016/j.ejps.2012.03.012 |
| Popis: | P-glycoprotein belongs to the ATP binding cassette transporters, responsible for the multidrug resistance of cancer cells. These transporters efflux hydrophobic drugs outside cells and decrease their therapeutic efficacy. The aim of this study was to investigate the effect of vandetanib, an oral tyrosine kinase inhibitor of EGFR, VEGFR 2 and RET kinases, on the functionality of P-gp after a 24 h-treatment at therapeutic concentration (2 μM), and its ability to increase the cytotoxicity of chemotherapeutic agents in multidrug resistance cancer cells. In this study we found that IGROV1-DXR and IGROV1-CDDP cells were resistant to doxorubicin and cisplatin respectively, compare to parental cell line IGROV1. The parental sensitive and the two resistant cell lines similarly expressed MRP1 and did not express BCRP. Moreover, in contrast to the IGROV1 and IGROV1-CDDP cells, IGROV1-DXR cell line overexpressed P-gp. Functional activity studies demonstrated that MRP1 was not functional and the MDR phenotype in IGROV1-DXR cells was linked to P-gp functionality. Results also showed that vandetanib reversed resistance to doxorubicin in IGROV1-DXR cells, but not to cisplatin in IGROV1-CDDP cells. After 24 h of treatment, vandetanib increased the accumulation of rhodamine 123 and calcein AM, demonstrating a functional inhibition of the transporter. In IGROV1-DXR cell line, vandetanib reverse resistance to doxorubicin by inhibiting the functionality of P-gp. In conclusion, vandetanib should be an option for drug combination in patients already developing a P-gp mediated multidrug resistance. |
| Databáze: | OpenAIRE |
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