The B-cell lymphoma 2 (BCL2)-inhibitors, ABT-737 and ABT-263, are substrates for P-glycoprotein.

Abstract

Inhibition of BCL2 proteins is one of the most promising new approaches to targeted cancer therapy resulting in the induction of apoptosis. Amongst the most specific BCL2-inhibitors identified are ABT-737 and ABT-263. However, targeted therapy is often only effective for a limited amount of time because of the occurrence of drug resistance. In this study, the interaction of BCL2-inhibitors with the drug efflux transporter P-glycoprotein was investigated. Using (3)H labelled ABT-263, we found that cells with high P-glycoprotein activity accumulated less drug. In addition, cells with increased P-glycoprotein expression were more resistant to apoptosis induced by either ABT-737 or ABT-263. Addition of tariquidar or verapamil sensitized the cells to BCL2-inhibitor treatment, resulting in higher apoptosis. Our data suggest that the BCL2-inhibitors ABT-737 and ABT-263 are substrates for P-glycoprotein. Over-expression of P-glycoprotein may be, at least partly, responsible for resistance to these BCL2-inhibitors.

• Authors: Meike Vogler, David Dickens, Martin J S Dyer, Andrew Owen, Munir Pirmohamed, Gerald M Cohen
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 408 Issue 2 Pg. 344-9 (May 06 2011) ISSN: 1090-2104 [Electronic] United States
• PMID: 21514278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• ABT-737
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Aniline Compounds
• Biphenyl Compounds
• Nitrophenols
• Piperazines
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• navitoclax

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Aniline Compounds (metabolism, pharmacology)
• Animals
• Biphenyl Compounds (metabolism, pharmacology)
• Cell Line
• Dogs
• Nitrophenols (metabolism, pharmacology)
• Piperazines (metabolism, pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Substrate Specificity
• Sulfonamides (metabolism, pharmacology)