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Fluorescent Substrates for Flow Cytometric Evaluation of Efflux Inhibition in ABCB1, ABCC1, and ABCG2 Transporters.

Anal Biochem. 2013 Mar 4;

Authors: Jacob Strouse J, Ivnitski-Steele I, Waller A, Young SM, Perez D, Evangelisti AM, Ursu O, Bologa CG, Carter MB, Salas VM, Tegos G, Larson RS, Oprea TI, Edwards BS, Sklar LA


ATP binding cassette (ABC)3 transmembrane efflux pumps such as P-glycoprotein (ABCB1), multidrug resistance protein 1 (ABCC1), and breast cancer resistance protein (ABCG2) play an important role in anticancer drug resistance. A large number of structurally and functionally diverse compounds act as substrates or modulators of these pumps. In vitro assessment of the affinity of drug candidates for multidrug resistance proteins is central to predict in vivo pharmacokinetics and drug-drug interactions. The objective of this study was to identify and characterize new substrates for these transporters. As part of a collaborative project with Life Technologies™, 102 fluorescent probes were investigated in a flow cytometric screen of ABC transporters. The primary screen compared substrate efflux activity in parental cell lines to their corresponding highly expressing resistant counterparts. The fluorescent compound library included a range of excitation/emission profiles and required dual laser excitation as well as multiple fluorescence detection channels. A total of 31 substrates with active efflux in one or more pump, and practical fluorescence response ranges were identified and tested for interaction with 8 known inhibitors. This screening approach provides an efficient tool for identification and characterization of new fluorescent substrates for ABCB1, ABCC1, and ABCG2.

PMID: 23470221 [PubMed - as supplied by publisher]