PMID- 26536031 OWN - NLM STAT- MEDLINE DCOM- 20160627 LR - 20181202 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 10 IP - 11 DP - 2015 TI - Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines. PG - e0141795 LID - 10.1371/journal.pone.0141795 [doi] LID - e0141795 AB - BACKGROUND: 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. AIM: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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. FAU - Galetti, Maricla AU - Galetti M AD - Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. AD - Italian Workers' Compensation Authority (INAIL), Research Centre at the University of Parma, Parma, Italy. FAU - Petronini, Pier Giorgio AU - Petronini PG AD - Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. FAU - Fumarola, Claudia AU - Fumarola C AD - Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. FAU - Cretella, Daniele AU - Cretella D AD - Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. FAU - La Monica, Silvia AU - La Monica S AD - Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. FAU - Bonelli, Mara AU - Bonelli M AD - Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. FAU - Cavazzoni, Andrea AU - Cavazzoni A AD - Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. FAU - Saccani, Francesca AU - Saccani F AD - Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. FAU - Caffarra, Cristina AU - Caffarra C AD - Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. FAU - Andreoli, Roberta AU - Andreoli R AD - Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. FAU - Mutti, Antonio AU - Mutti A AD - Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. AD - Italian Workers' Compensation Authority (INAIL), Research Centre at the University of Parma, Parma, Italy. FAU - Tiseo, Marcello AU - Tiseo M AD - Division of Medical Oncology, University Hospital of Parma, Parma, Italy. FAU - Ardizzoni, Andrea AU - Ardizzoni A AD - Medical Oncology Unit, S. Orsola-Malpighi Hospital, Bologna, Italy. FAU - Alfieri, Roberta R AU - Alfieri RR AD - Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151104 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (ABCG2 protein, human) RN - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 2) RN - 0 (ATP-Binding Cassette Transporters) RN - 0 (Indoles) RN - 0 (Neoplasm Proteins) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Quinazolines) RN - 0 (RNA, Small Interfering) RN - CW5S8OP3VO (tryptoquivaline) RN - EC 2.7.10.1 (ErbB Receptors) RN - S65743JHBS (Gefitinib) SB - IM MH - ATP Binding Cassette Transporter, Subfamily G, Member 2 MH - ATP-Binding Cassette Transporters/antagonists & inhibitors/genetics/*metabolism MH - Biological Transport MH - Carcinoma, Non-Small-Cell Lung/metabolism/pathology MH - Cell Line, Tumor MH - Chromatography, High Pressure Liquid MH - ErbB Receptors/genetics MH - Gefitinib MH - Gene Expression Regulation/*drug effects MH - HEK293 Cells MH - Humans MH - Indoles/pharmacology MH - Lung Neoplasms/metabolism/pathology MH - Neoplasm Proteins/antagonists & inhibitors/genetics/*metabolism MH - Protein Kinase Inhibitors/analysis/*toxicity MH - Quinazolines/analysis/*toxicity MH - RNA Interference MH - RNA, Small Interfering/metabolism MH - Tandem Mass Spectrometry PMC - PMC4633241 COIS- Competing Interests: The authors confirm that co-author Pier Giorgio Petronini is a PLOS ONE Editorial Board member. This does not alter the authors' adherence to PLOS ONE Editorial policies and criteria. EDAT- 2015/11/05 06:00 MHDA- 2016/06/28 06:00 PMCR- 2015/11/04 CRDT- 2015/11/05 06:00 PHST- 2014/11/10 00:00 [received] PHST- 2015/10/13 00:00 [accepted] PHST- 2015/11/05 06:00 [entrez] PHST- 2015/11/05 06:00 [pubmed] PHST- 2016/06/28 06:00 [medline] PHST- 2015/11/04 00:00 [pmc-release] AID - PONE-D-14-50533 [pii] AID - 10.1371/journal.pone.0141795 [doi] PST - epublish SO - PLoS One. 2015 Nov 4;10(11):e0141795. doi: 10.1371/journal.pone.0141795. eCollection 2015.