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Title: The B-cell lymphoma 2 (BCL2)-inhibitors, ABT-737 and ABT-263, are substrates for P-glycoprotein.
Authors: Vogler, M
Dickens, D
Dyer, MJ
Owen, A
Pirmohamed, M
Cohen, GM
First Published: 6-May-2011
Citation: BIOCHEM BIOPHYS RES COMMUN, 2011, 408 (2), pp. 344-349
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.
DOI Link: 10.1016/j.bbrc.2011.04.043
eISSN: 1090-2104
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine

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