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: Gisela Caceres, Robert W Robey, Lubomir Sokol, Kathy L McGraw, Justine Clark, Nicholas J Lawrence, Said M Sebti, Michael Wiese, Alan F List
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 16 Pg. 4204-13 (Aug 15 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22761337 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Quinolines

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology)
• Drug Interactions
• Drug Resistance, Neoplasm
• Female
• HEK293 Cells
• Humans
• K562 Cells
• Mice
• Mice, SCID
• Quinolines (pharmacology)