title: Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.|Italian Workers' Compensation Authority (INAIL), Research Centre at the University of Parma, Parma, Italy.
authors.forename: Maricla
authors.initials: M
authors.lastname: Galetti
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Petronini
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fumarola
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cretella
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: La Monica
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Bonelli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavazzoni
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Saccani
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Caffarra
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Andreoli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.|Italian Workers' Compensation Authority (INAIL), Research Centre at the University of Parma, Parma, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mutti
authors.affiliation: Division of Medical Oncology, University Hospital of Parma, Parma, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Tiseo
authors.affiliation: Medical Oncology Unit, S. Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ardizzoni
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Roberta R
authors.initials: RR
authors.lastname: Alfieri
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D066246:ErbB Receptors / Q000235:genetics; D000077156:Gefitinib; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000032:analysis / Q000633:toxicity*; D011799:Quinazolines / Q000032:analysis / Q000633:toxicity*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D007211:Indoles; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; C010522:tryptoquivaline; D066246:ErbB Receptors; D000077156:Gefitinib