PloS one, 2015-11, Vol.10 (11), p.e0141795-e0141795
2015
Details
- Autor(en) / Beteiligte
- Titel
- Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines
- Ist Teil von
- PloS one, 2015-11, Vol.10 (11), p.e0141795-e0141795
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2015
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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. 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. 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. 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0141795Titel-ID: cdi_plos_journals_1730277695
- Format
- –
- Schlagworte
- ABC transporters, Accumulation, ATP Binding Cassette Transporter, Sub-Family G, Member 2, ATP-Binding Cassette Transporters - antagonists & inhibitors, ATP-Binding Cassette Transporters - genetics, ATP-Binding Cassette Transporters - metabolism, Binding sites, Biological Transport, Biotechnology, Breast cancer, Cancer, Cancer therapies, Carcinoma, Non-Small-Cell Lung - metabolism, Carcinoma, Non-Small-Cell Lung - pathology, Care and treatment, Cell culture, Cell Line, Tumor, Chemotherapy, Chromatography, High Pressure Liquid, Development and progression, Drug resistance, Efflux, Enzyme inhibitors, Epidermal growth factor, Epidermal growth factor receptors, Gefitinib, Gene Expression Regulation - drug effects, Genes, Genetic aspects, Glutamine, Health aspects, HEK293 Cells, Humans, Indoles - pharmacology, Inhibitor drugs, Inhibitors, Intracellular, Kinases, Leukemia, Lung cancer, Lung cancer, Non-small cell, Lung diseases, Lung Neoplasms - metabolism, Lung Neoplasms - pathology, Medicine, Metabolism, Metabolites, Multidrug resistance, Mutation, Neoplasm Proteins - antagonists & inhibitors, Neoplasm Proteins - genetics, Neoplasm Proteins - metabolism, Non-small cell lung cancer, Non-small cell lung carcinoma, Nutrient transport, Patient outcomes, Protein Kinase Inhibitors - analysis, Protein Kinase Inhibitors - toxicity, Protein-tyrosine kinase, Proteins, Quinazolines - analysis, Quinazolines - toxicity, Receptor, Epidermal Growth Factor - genetics, RNA Interference, RNA, Small Interfering - metabolism, Rodents, Substrate inhibition, Substrates, Tandem Mass Spectrometry, Tumors, Tyrosine