title: HG-829 is a potent noncompetitive inhibitor of the ATP-binding cassette multidrug resistance transporter ABCB1.
abstract: Transmembrane drug export mediated by the ATP-binding cassette (ABC) transporter P-glycoprotein contributes to clinical resistance to antineoplastics. In this study, we identified the substituted quinoline HG-829 as a novel, noncompetitive, and potent P-glycoprotein inhibitor that overcomes in vitro and in vivo drug resistance. We found that nontoxic concentrations of HG-829 restored sensitivity to P-glycoprotein oncolytic substrates. In ABCB1-overexpressing cell lines, HG-829 significantly enhanced cytotoxicity to daunorubicin, paclitaxel, vinblastine, vincristine, and etoposide. Coadministration of HG-829 fully restored in vivo antitumor activity of daunorubicin in mice without added toxicity. Functional assays showed that HG-829 is not a Pgp substrate or competitive inhibitor of Pgp-mediated drug efflux but rather acts as a noncompetitive modulator of P-glycoprotein transport function. Taken together, our findings indicate that HG-829 is a potent, long-acting, and noncompetitive modulator of P-glycoprotein export function that may offer therapeutic promise for multidrug-resistant malignancies.
authors: Experimental Therapeutics, Moffitt Cancer Center, University of South Florida, Tampa, Florida 33612, USA.
authors: Gisela
authors: G
authors: Caceres
authors: Robert W
authors: RW
authors: Robey
authors: Lubomir
authors: L
authors: Sokol
authors: Kathy L
authors: KL
authors: McGraw
authors: Justine
authors: J
authors: Clark
authors: Nicholas J
authors: NJ
authors: Lawrence
authors: Said M
authors: SM
authors: Sebti
authors: Michael
authors: M
authors: Wiese
authors: Alan F
authors: AF
authors: List
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D020014:K562 Cells; D051379:Mice; D016513:Mice, SCID; D011804:Quinolines / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011804:Quinolines