Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines.
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 ki...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4633241?pdf=render |
| _version_ | 1819087162384056320 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Maricla Galetti |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T21:31:46Z |
| format | Article |
| id | doaj.art-2a537f4321f24691812b903183ae21a9 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T21:31:46Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-2a537f4321f24691812b903183ae21a92022-12-21T18:49:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-011011e014179510.1371/journal.pone.0141795Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines.Maricla GalettiPier Giorgio PetroniniClaudia FumarolaDaniele CretellaSilvia La MonicaMara BonelliAndrea CavazzoniFrancesca SaccaniCristina CaffarraRoberta AndreoliAntonio MuttiMarcello TiseoAndrea ArdizzoniRoberta R AlfieriBCRP/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.http://europepmc.org/articles/PMC4633241?pdf=render |
| spellingShingle | 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 Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines. PLoS ONE |
| title | Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines. |
| title_full | Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines. |
| title_fullStr | Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines. |
| title_full_unstemmed | Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines. |
| title_short | Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines. |
| title_sort | effect of abcg2 bcrp expression on efflux and uptake of gefitinib in nsclc cell lines |
| url | http://europepmc.org/articles/PMC4633241?pdf=render |
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