Galetti, Maricla Petronini, Pier Giorgio Fumarola, Claudia Cretella, Daniele Monica, Silvia La Bonelli, Mara Cavazzoni, Andrea Saccani, Francesca Caffarra, Cristina Andreoli, Roberta Mutti, Antonio Tiseo, Marcello Ardizzoni, Andrea Alfieri, Roberta R. Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines <div><p>Background</p><p>BCRP/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.</p><p>Aim</p><p>The 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.</p><p>Methods and Results</p><p>Our 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.</p><p>Conclusions</p><p>Therefore, 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.</p></div> ABCG 2 plasma membrane levels;ABCG 2;efflux transporter ABCG 2;uptake;intracellular gefitinib content;tyrosine kinase inhibitors;cell lung cancer;intracellular gefitinib accumulation;ABCG 2 overexpression;cancer chemotherapeutic agents;multidrug resistance protein;EGFR Tyrosine Kinase Inhibitor;drug transport systems;mpp;NSCLC cell lines;lung cancer cells;ABCG 2 activity 2015-11-04
    https://plos.figshare.com/articles/dataset/_Effect_of_ABCG2_BCRP_Expression_on_Efflux_and_Uptake_of_Gefitinib_in_NSCLC_Cell_Lines_/1594583
10.1371/journal.pone.0141795