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1. Biochem Pharmacol. 2012 Mar 7. [Epub ahead of print]

GW583340 and GW2974, human EGFR and HER-2 inhibitors, reverse ABCG2- and
ABCB1-mediated drug resistance.

Sodani K, Tiwari AK, Singh S, Patel A, Xiao ZJ, Chen JJ, Sun YL, Talele TT, Chen
ZS.

Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health
Professions, St. John's University, Queens, NY 11439, USA.

The overexpression of ATP binding cassette (ABC) transporters often leads to the
development of multidrug resistance (MDR) and results in a suboptimal response to
chemotherapy. Previously, we reported that lapatinib (GW572016), a human
epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinase inhibitor
(TKI), significantly reverses MDR in cancer cells by blocking the efflux function
of ABC subfamily B member 1 (ABCB1)- and ABC subfamily G member 2
(ABCG2)-mediated MDR. In the present study, we conducted in vitro experiments to
evaluate if GW583340 and GW2974, structural analogues of lapatinib, could reverse
ABCB1- and ABCG2-mediated MDR. Our results showed that GW583340 and GW2974
significantly sensitized ABCB1 and ABCG2 overexpressing MDR cells to their
anticancer substrates. GW583340 and GW2974 significantly increased the
intracellular accumulation of [(3)H]-paclitaxel in ABCB1 overexpressing cells and
[(3)H]-mitoxantrone in ABCG2 overexpressing cells respectively. In addition,
GW583340 and GW2974 significantly inhibited ABCG2-mediated transport of
methotrexate in ABCG2 overexpressing membrane vesicles. There was no significant
change in the expression levels of ABCB1 and ABCG2 in the cell lines exposed to
5μM of either GW583340 or GW2974 for 3 days. In addition, a docking model
predicted the binding conformation of GW583340 and GW2974 to be within the
transmembrane region of homology modeled human ABCB1 and ABCG2. We conclude that
GW583340 and GW2974, at clinically achievable plasma concentrations, reverse
ABCB1- and ABCG2-mediated MDR by blocking the drug efflux function of these
transporters. These findings may be useful in developing combination therapy for
cancer treatment with EGFR TKIs.

Copyright © 2012. Published by Elsevier Inc.

PMID: 22414725 [PubMed - as supplied by publisher]