title: 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.affiliation: MRC Toxicology Unit, University of Leicester, LE1 9HN Leicester, United Kingdom. mv62@le.ac.uk
authors.forename: Meike
authors.initials: M
authors.lastname: Vogler
authors.forename: David
authors.initials: D
authors.lastname: Dickens
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Cohen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000814:Aniline Compounds / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D009596:Nitrophenols / Q000378:metabolism* / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity; D013449:Sulfonamides / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C501332:ABT-737; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000814:Aniline Compounds; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C528561:navitoclax