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Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter

Overexpression of adenine triphosphate (ATP)-binding cassette (ABC) transporters is one of the main reasons of multidrug resistance (MDR) in cancer cells. Trametinib, a novel specific small-molecule mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, is currently used for the tr...

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Autores principales: Qiu, Jian-Ge, Zhang, Yao-Jun, Li, Yong, Zhao, Jin-Ming, Zhang, Wen-Ji, Jiang, Qi-Wei, Mei, Xiao-Long, Xue, You-Qiu, Qin, Wu-Ming, Yang, Yang, Zheng, Di-Wei, Chen, Yao, Wei, Meng-Ning, Shi, Zhi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558166/
https://www.ncbi.nlm.nih.gov/pubmed/25915534
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author Qiu, Jian-Ge
Zhang, Yao-Jun
Li, Yong
Zhao, Jin-Ming
Zhang, Wen-Ji
Jiang, Qi-Wei
Mei, Xiao-Long
Xue, You-Qiu
Qin, Wu-Ming
Yang, Yang
Zheng, Di-Wei
Chen, Yao
Wei, Meng-Ning
Shi, Zhi
author_facet Qiu, Jian-Ge
Zhang, Yao-Jun
Li, Yong
Zhao, Jin-Ming
Zhang, Wen-Ji
Jiang, Qi-Wei
Mei, Xiao-Long
Xue, You-Qiu
Qin, Wu-Ming
Yang, Yang
Zheng, Di-Wei
Chen, Yao
Wei, Meng-Ning
Shi, Zhi
author_sort Qiu, Jian-Ge
collection PubMed
description Overexpression of adenine triphosphate (ATP)-binding cassette (ABC) transporters is one of the main reasons of multidrug resistance (MDR) in cancer cells. Trametinib, a novel specific small-molecule mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, is currently used for the treatment of melanoma in clinic. In this study, we investigated the effect of trametinib on MDR mediated by ABC transporters. Trametinib significantly potentiated the effects of two ABCB1 substrates vincristine and doxorubicin on inhibition of growth, arrest of cell cycle and induction of apoptosis in cancer cells overexpressed ABCB1, but not ABCC1 and ABCG2. Furthermore, trametinib did not alter the sensitivity of non-ABCB1 substrate cisplatin. Mechanistically, trametinib potently blocked the drug-efflux activity of ABCB1 to increase the intracellular accumulation of rhodamine 123 and doxorubicin and stimulates the ATPase of ABCB1 without alteration of the expression of ABCB1. Importantly, trametinib remarkably enhanced the effect of vincristine against the xenografts of ABCB1-overexpressing cancer cells in nude mice. The predicted binding mode showed the hydrophobic interactions of trametinib within the large drug binding cavity of ABCB1. Consequently, our findings may have important implications for use of trametinib in combination therapy for cancer treatment.
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spelling pubmed-45581662015-09-09 Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter Qiu, Jian-Ge Zhang, Yao-Jun Li, Yong Zhao, Jin-Ming Zhang, Wen-Ji Jiang, Qi-Wei Mei, Xiao-Long Xue, You-Qiu Qin, Wu-Ming Yang, Yang Zheng, Di-Wei Chen, Yao Wei, Meng-Ning Shi, Zhi Oncotarget Research Paper Overexpression of adenine triphosphate (ATP)-binding cassette (ABC) transporters is one of the main reasons of multidrug resistance (MDR) in cancer cells. Trametinib, a novel specific small-molecule mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, is currently used for the treatment of melanoma in clinic. In this study, we investigated the effect of trametinib on MDR mediated by ABC transporters. Trametinib significantly potentiated the effects of two ABCB1 substrates vincristine and doxorubicin on inhibition of growth, arrest of cell cycle and induction of apoptosis in cancer cells overexpressed ABCB1, but not ABCC1 and ABCG2. Furthermore, trametinib did not alter the sensitivity of non-ABCB1 substrate cisplatin. Mechanistically, trametinib potently blocked the drug-efflux activity of ABCB1 to increase the intracellular accumulation of rhodamine 123 and doxorubicin and stimulates the ATPase of ABCB1 without alteration of the expression of ABCB1. Importantly, trametinib remarkably enhanced the effect of vincristine against the xenografts of ABCB1-overexpressing cancer cells in nude mice. The predicted binding mode showed the hydrophobic interactions of trametinib within the large drug binding cavity of ABCB1. Consequently, our findings may have important implications for use of trametinib in combination therapy for cancer treatment. Impact Journals LLC 2015-04-14 /pmc/articles/PMC4558166/ /pubmed/25915534 Text en Copyright: © 2015 Qiu et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Qiu, Jian-Ge
Zhang, Yao-Jun
Li, Yong
Zhao, Jin-Ming
Zhang, Wen-Ji
Jiang, Qi-Wei
Mei, Xiao-Long
Xue, You-Qiu
Qin, Wu-Ming
Yang, Yang
Zheng, Di-Wei
Chen, Yao
Wei, Meng-Ning
Shi, Zhi
Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter
title Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter
title_full Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter
title_fullStr Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter
title_full_unstemmed Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter
title_short Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter
title_sort trametinib modulates cancer multidrug resistance by targeting abcb1 transporter
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558166/
https://www.ncbi.nlm.nih.gov/pubmed/25915534
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