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1. ChemMedChem. 2012 Feb 22. doi: 10.1002/cmdc.201100543. [Epub ahead of print]

Tyrosine Kinase Inhibitors Influence ABCG2 Expression in EGFR-Positive MDCK BCRP
Cells via the PI3K/Akt Signaling Pathway.

Pick A, Wiese M.

Institute of Pharmacy, University of Bonn, An der Immenburg 4, 53121 Bonn
(Germany).

Multidrug resistance observed in cancer chemotherapy is commonly attributed to
overexpression of efflux transporter proteins. These proteins act as
ATP-dependent drug efflux pumps, actively extruding chemotherapeutic agents from
cells and causing a decrease in intracellular drug accumulation. Besides the
well-recognized role of P-glycoprotein (P-gp, ABCB1), the breast cancer
resistance protein (BCRP, ABCG2) is becoming increasingly accepted as playing an
important role in multidrug resistance. In contrast to P-glycoprotein, only a few
inhibitors of ABCG2 are known. According to the literature, tyrosine kinase
inhibitors (TKIs) can be considered to be broad-spectrum inhibitors, interacting
with ABCB1, ABCC1 and ABCG2. Here, we investigated seven different TKIs,
gefitinib, erlotinib, AG1478, PD158780, PD153035, nilotinib and imatinib, for
their potential to restore ABCG2 sensitivity to cells. Furthermore, we analyzed
the alteration of ABCG2 expression caused by TKIs and demonstrated that EGFR
inhibitors such as gefitinib and PD158780 reduced both total and surface
expression of ABCG2 in EGRF-positive MDCK BCRP cells by interaction with the
PI3K/Akt signaling pathway. The reduced ABCG2 content led to an increased effect
of XR9577, a well-known ABCG2 modulator, lowering the concentration required for
half maximal inhibition. On the other hand, BCR-ABL inhibitors had no influence
on ABCG2 expression and modulator activity. Interestingly, a combination of an
EGFR inhibitor with the PI3K/Akt inhibitor LY294002 led to a significant
reduction of ABCG2 expression at low concentrations of the drugs. Based on our
results, we assume that EGFR exerts a post-transcriptional enhancing effect on
ABCG2 expression via the PI3K/Akt signaling pathway, which can be attenuated by
EGFR inhibitors. Blocking the key signaling pathway regulating ABCG2 expression
with EGFR inhibitors, combined with the inhibition of ABCG2 with potent
modulators might be a promising approach to circumvent MDR in cancer cells.

Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PMID: 22354538 [PubMed - as supplied by publisher]