title: Elacridar enhances the cytotoxic effects of sunitinib and prevents multidrug resistance in renal carcinoma cells.
abstract: Intrinsic drug resistance occurs in many renal carcinomas and is associated with increased expression of multidrug resistant proteins, which inhibits intracellular drug accumulation. Multidrug resistant protein 1, also known as P-glycoprotein, is a membrane drug efflux pump belonging to the ATP-binding cassette (ABC) transporter superfamily. ABC Sub-family B Member 2 (ABCG2) is widely distributed and is involved in the multidrug resistant phenotype. Sunitinib is a tyrosine kinase inhibitor used to treat kidney cancer that disrupts signaling pathways responsible for abnormal cancer cell proliferation and tumor angiogenesis. Multiple drug resistance is important in tyrosine kinase inhibitor-induced resistance. We hypothesized that inhibition of multidrug resistant transporters by elacridar (dual inhibitor of P-glycoprotein and ABCG 2) might overcome sunitinib resistance in experimental renal cell carcinoma. Human renal carcinoma cell lines 786-O, ACHN, and Caki-1 were treated with sunitinib or elacridar alone, or in combination. We showed that elacridar significantly enhanced sunitinib cytotoxicity in 786-O cells. P-glycoprotein activity, confirmed by P-glycoprotein function assay, was found to be inhibited by elacridar. ABCG2 expression was low in all renal carcinoma cell lines, and was suppressed only by combination treatment in 786-O cells. ABCG2 function was inhibited by sunitinib alone or combination with elacridar but not elacridar alone. These findings suggest that sunitinib resistance involves multidrug resistance transporters, and in combination with elacridar, can be reversed in renal carcinoma cells by P-glycoprotein inhibition.
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. Electronic address: hiromi-s@chiba-u.jp.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Sana
authors.initials: S
authors.lastname: Siddig
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Miaki
authors.initials: M
authors.lastname: Uzu
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Sayumi
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Practical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nomura
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kashiba
authors.affiliation: Department of Practical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Gushimiyagi
authors.affiliation: Department of Practical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekine
authors.affiliation: Department of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Uehara
authors.affiliation: Department of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Arano
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yamaura
authors.affiliation: Center for Preventive Medical Science, Chiba University, Chiba, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ueno
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000166:Acridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000819:agonists* / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism; D007700:Kinetics; D049990:Membrane Transport Modulators / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000819:agonists* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D000077210:Sunitinib; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D000970:Antineoplastic Agents; D007211:Indoles; D049990:Membrane Transport Modulators; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D044005:Tetrahydroisoquinolines; C083501:Elacridar; D000077210:Sunitinib
keywords: ABCG2; Drug resistance; P-glycoprotein; Renal cell carcinoma; Sunitinib; Sunitinib (Sutent) (PubChem CID: 5329102)