Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines
Maricla Galetti
Pier Giorgio Petronini
Claudia Fumarola
Daniele Cretella
Silvia La Monica
Mara Bonelli
Andrea Cavazzoni
Francesca Saccani
Cristina Caffarra
Roberta Andreoli
Antonio Mutti
Marcello Tiseo
Andrea Ardizzoni
Roberta R. Alfieri
10.1371/journal.pone.0141795
https://plos.figshare.com/articles/dataset/_Effect_of_ABCG2_BCRP_Expression_on_Efflux_and_Uptake_of_Gefitinib_in_NSCLC_Cell_Lines_/1594583
<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>
2015-11-04 06:20:32
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