Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines

Abstract

BackgroundBCRP/ABCG2 emerged as an important multidrug resistance protein, because it confers resistance to several classes of cancer chemotherapeutic agents and to a number of novel molecularly-targeted therapeutics such as tyrosine kinase inhibitors. Gefitinib is an orally active, selective EGFR tyrosine kinase inhibitor used in the treatment of patients with advanced non small cell lung cancer (NSCLC) carrying activating EGFR mutations. Membrane transporters may affect the distribution and accumulation of gefitinib in tumour cells; in particular a reduced intracellular level of the drug may result from poor uptake, enhanced efflux or increased metabolism.AimThe present study, performed in a panel of NSCLC cell lines expressing different ABCG2 plasma membrane levels, was designed to investigate the effect of the efflux transporter ABCG2 on intracellular gefitinib accumulation, by dissecting the contribution of uptake and efflux processes.Methods and ResultsOur findings indicate that gefitinib, in lung cancer cells, inhibits ABCG2 activity, as previously reported. In addition, we suggest that ABCG2 silencing or overexpression affects intracellular gefitinib content by modulating the uptake rather than the efflux. Similarly, overexpression of ABCG2 affected the expression of a number of drug transporters, altering the functional activities of nutrient and drug transport systems, in particular inhibiting MPP, glucose and glutamine uptake.ConclusionsTherefore, we conclude that gefitinib is an inhibitor but not a substrate for ABCG2 and that ABCG2 overexpression may modulate the expression and activity of other transporters involved in the uptake of different substrates into the cells.

TKI combination therapy: strategy to enhance dasatinib uptake by inhibiting Pgp‐ and BCRP‐mediated efflux

“…Enhanced efflux of TKIs by over‐expression of Pgp and BCRP in cancer cells has been implicated to be an important resistance mechanism and is responsible for the poor chemotherapeutic response . Accumulating evidence continues to show that numerous TKIs are dual substrates of Pgp and BCRP and in addition, many of them have also been found to be inhibitors of Pgp and BCRP .…”

Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)

“…In recent years, TKIs have been identified as inhibitors of several ATP-binding cassette (ABC) efflux transporters that are commonly upregulated in cancer cells including P-glycoprotein (multidrug resistance protein 1), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein (MRP) 1 [10][11][12][13][14][15][16][17][18]. ABC efflux transporters consist of a large family of membrane-spanning proteins involved in the active extrusion of substrates such as endogenous molecules, drugs, and drug metabolites from the cell through hydrolysis of ATP [19][20][21].…”

Subcellular localization of several structurally different tyrosine kinase inhibitors

“…For erlotinib it is likely that it is transported into the membrane, binds to its target, but is effluxed before it can enter the cell [19]. In contrast, the other EGFR targeted drug (gefitinib) is taken up by an active transporter [13,20,21] and subsequently trapped in the cell. Sorafenib is not only actively being transported into the cell but is possibly also trapped in the cell, either as the parent drug or as a metabolite, since it is substrate for various Phase I and Phase II enzymes [22,23].…”