title: PDE5 inhibitors, sildenafil and vardenafil, reverse multidrug resistance by inhibiting the efflux function of multidrug resistance protein 7 (ATP-binding Cassette C10) transporter.
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 [(3)H]-paclitaxel by inhibiting the efflux of [(3 H]-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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St John's University, Jamaica, New York, USA.
authors.forename: Jun-Jiang
authors.initials: JJ
authors.lastname: Chen
authors.forename: Yue-Li
authors.initials: YL
authors.lastname: Sun
authors.forename: Amit K
authors.initials: AK
authors.lastname: Tiwari
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Xiao
authors.forename: Kamlesh
authors.initials: K
authors.lastname: Sodani
authors.forename: Dong-Hua
authors.initials: DH
authors.lastname: Yang
authors.forename: Saraubh G
authors.initials: SG
authors.lastname: Vispute
authors.forename: Wen-Qi
authors.initials: WQ
authors.lastname: Jiang
authors.forename: Si-Dong
authors.initials: SD
authors.lastname: Chen
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015151:Immunoblotting; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; C421142:ABCC10 protein, human