• Open Access

PDE5 inhibitors, sildenafil and vardenafil, reverse multidrug resistance by inhibiting the efflux function of multidrug resistance protein 7 (ATP-binding Cassette C10) transporter

Authors

  • Jun-Jiang Chen,

    1. Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York, USA
    2. Guangdong Key Laboratory for Molecular Epidemiology, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
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  • Yue-Li Sun,

    1. Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York, USA
    2. Department of Medical Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou, China
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  • Amit K. Tiwari,

    1. Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York, USA
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  • Zhi-Jie Xiao,

    1. Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York, USA
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  • Kamlesh Sodani,

    1. Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York, USA
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  • Dong-Hua Yang,

    1. Biosample Repository, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
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  • Saraubh G. Vispute,

    1. Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York, USA
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  • Wen-Qi Jiang,

    1. Department of Medical Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou, China
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  • Si-Dong Chen,

    Corresponding author
    1. Guangdong Key Laboratory for Molecular Epidemiology, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
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  • Zhe-Sheng Chen

    Corresponding author
    1. Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York, USA
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Abstract

Phosphodiesterase type 5 (PDE5) inhibitors are widely used in the treatment of male erectile dysfunction and pulmonary hypertension. Recently, several groups have evaluated the ability of PDE5 inhibitors for their anticancer activities. Previously, we had shown that sildenafil, vardenafil and tadalafil could reverse P-glycoprotein (ATP-binding cassette B1)-mediated MDR. In the present study, we determined whether these PDE5 inhibitors have the potential to reverse multidrug resistance protein 7 (MRP7; ATP-binding cassette C10)-mediated MDR. We found that sildenafil and vardenafil dose-dependently enhanced the sensitivity of MRP7-transfected HEK293 cells to paclitaxel, docetaxel and vinblastine, while tadalafil had only a minimal effect. Accumulation and efflux experiments demonstrated that sildenafil and vardenafil increased the intracellular accumulation of [3H]-paclitaxel by inhibiting the efflux of [3H]-paclitaxel in HEK/MRP7 cells. In addition, immunoblot and immunofluorescence analyses indicated that no significant alterations of MRP7 protein expression and localization in plasma membranes were found after treatment with sildenafil, vardenafil or tadalafil. These results demonstrate that sildenafil and vardenafil reverse MRP7-mediated a MDR through inhibition of the drug efflux function of MRP7. Our findings indicate a potentially novel use of PDE5 inhibitors as an adjuvant chemotherapeutic agent in clinical practice. (Cancer Sci, doi: 10.1111/j.1349-7006.2012.02328.x, 2012)

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