title: Sildenafil reverses ABCB1- and ABCG2-mediated chemotherapeutic drug resistance.
abstract: Sildenafil is a potent and selective inhibitor of the type 5 cGMP (cyclic guanosine 3',5'-monophosphate)-specific phosphodiesterase that is used clinically to treat erectile dysfunction and pulmonary arterial hypertension. Here, we report that sildenafil has differential effects on cell surface ABC transporters such as ABCB1, ABCC1, and ABCG2 that modulate intracompartmental and intracellular concentrations of chemotherapeutic drugs. In ABCB1-overexpressing cells, nontoxic doses of sildenafil inhibited resistance and increased the effective intracellular concentration of ABCB1 substrate drugs such as paclitaxel. Similarly, in ABCG2-overexpressing cells, sildenafil inhibited resistance to ABCG2 substrate anticancer drugs, for example, increasing the effective intracellular concentration of mitoxantrone or the fluorescent compound BODIPY-prazosin. Sildenafil also moderately inhibited the transport of E(2)17βG and methotrexate by the ABCG2 transporter. Mechanistic investigations revealed that sildenafil stimulated ABCB1 ATPase activity and inhibited photolabeling of ABCB1 with [(125)I]-iodoarylazidoprazosin (IAAP), whereas it only slightly stimulated ABCG2 ATPase activity and inhibited photolabeling of ABCG2 with [(125)I]-IAAP. In contrast, sildenafil did not alter the sensitivity of parental, ABCB1-, or ABCG2-overexpressing cells to non-ABCB1 and non-ABCG2 substrate drugs, nor did sildenafil affect the function of another ABC drug transporter, ABCC1. Homology modeling predicted the binding conformation of sildenafil within the large cavity of the transmembrane region of ABCB1. Overall, we found that sildenafil inhibits the transporter function of ABCB1 and ABCG2, with a stronger effect on ABCB1. Our findings suggest a possible strategy to enhance the distribution and potentially the activity of anticancer drugs by jointly using a clinically approved drug with known side effects and drug-drug interactions.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St John's University, Queens, New York 10016, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Shi
authors.forename: Amit K
authors.initials: AK
authors.lastname: Tiwari
authors.forename: Suneet
authors.initials: S
authors.lastname: Shukla
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.forename: Satyakam
authors.initials: S
authors.lastname: Singh
authors.forename: In-Wha
authors.initials: IW
authors.lastname: Kim
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.forename: Xingxiang
authors.initials: X
authors.lastname: Peng
authors.forename: Ioana
authors.initials: I
authors.lastname: Abraham
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Fu
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D001896:Boron Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007624:KB Cells; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology; D008942:Mitoxantrone / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011224:Prazosin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases; D001896:Boron Compounds; D008727:Methotrexate; D008942:Mitoxantrone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D017239:Paclitaxel; D010879:Piperazines; D011224:Prazosin; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; C116614:ABCG2 protein, human; C412306:BODIPY-FL prazosin; C421109:multidrug resistance-associated protein 1