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Chemotherapy sensitivity recovery of prostate cancer cells by functional inhibition and knock down of multidrug resistance proteins

Authors

  • Catherine Sánchez,

    1. Laboratory of Molecular and Cellular Andrology, Physiology and Biophysics Department, Faculty of Medicine, University of Chile, Santiago, Chile
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  • Alejandro Mercado,

    1. Laboratory of Molecular and Cellular Andrology, Physiology and Biophysics Department, Faculty of Medicine, University of Chile, Santiago, Chile
    2. Urology Service, Clinical Hospital University of Chile, Santiago, Chile
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  • Héctor R. Contreras,

    1. Laboratory of Molecular and Cellular Andrology, Physiology and Biophysics Department, Faculty of Medicine, University of Chile, Santiago, Chile
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  • Patricia Mendoza,

    1. Laboratory of Molecular and Cellular Andrology, Physiology and Biophysics Department, Faculty of Medicine, University of Chile, Santiago, Chile
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  • Juan Cabezas,

    1. Urology Service, Clinical Hospital University of Chile, Santiago, Chile
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  • Cristian Acevedo,

    1. Urology Service, Clinical Hospital University of Chile, Santiago, Chile
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  • Christian Huidobro,

    1. Urology Service, Clinical Hospital University of Chile, Santiago, Chile
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  • Enrique A. Castellón

    Corresponding author
    1. Laboratory of Molecular and Cellular Andrology, Physiology and Biophysics Department, Faculty of Medicine, University of Chile, Santiago, Chile
    • Laboratory of Molecular and Cellular Andrology, Physiology and Biophysics Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, P.O. Box 70005, Postal Code 8380453, Santiago, Chile.
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Abstract

BACKGROUND

In several cancer types, expression of multidrug resistance (MDR) proteins has been associated with lack of chemotherapy response. In advanced prostate cancer (PCa) the use of chemotherapy is mainly palliative due to its high resistance. Previously, we described that MDR phenotype in PCa could be related with high basal and drug-induced expression of MDR proteins P-Glycoprotein (P-Gp), MRP1, and LRP.

METHODS

Using primary cell cultures from PCa patients, we evaluated the effect of function and expression inhibition of P-Gp, MRP1, and LRP, on cell survival after chemotherapy exposure. Cells were treated with specific MDR protein substrates (docetaxel and mitoxantrone for P-Gp, methotrexate for MRP1 and cisplatin for LRP) and pharmacological inhibitors (cyclosporine A, genistein and 3-aminobenzamide), and cell survival was evaluated trough 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cell cycle analysis. MRP1 activity was evaluated by FACS using the specific inhibitor MK571. Cells were transfected with MDR proteins siRNAs and treated with the corresponding substrates.

RESULTS

PCa cell resistance to MDR protein substrates was partially reversed, decreasing cell survival in around 20%, by treating primary cell cultures with specific pharmacological inhibitors. PCa cells transfected with siRNAs against MDR proteins decreased cell survival when treated with the corresponding drugs. Docetaxel was the most effective chemotherapeutic drug to induce cell death and decrease survival.

CONCLUSION

Low chemotherapy response in PCa could be explained, in part, by over-expression of functional MDR proteins. Expression and function of these proteins should be evaluated to enhance efficacy of docetaxel-based therapies of patients with hormone-resistant PCa. Prostate 71:1810–1817, 2011. © 2011 Wiley Periodicals, Inc.

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