Cargando…

Olmutinib (BI1482694/HM61713), a Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Reverses ABCG2-Mediated Multidrug Resistance in Cancer Cells

The main characteristic of tumor cell resistance is multidrug resistance (MDR). MDR is the principle cause of the decline in clinical efficacy of chemotherapeutic drugs. There are several mechanisms that could cause MDR. Among these, one of the most important mechanisms underlying MDR is the overexp...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Wei, Fan, Ying-Fang, Cai, Chao-Yun, Wang, Jing-Quan, Teng, Qiu-Xu, Lei, Zi-Ning, Zeng, Leli, Gupta, Pranav, Chen, Zhe-Sheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189370/
https://www.ncbi.nlm.nih.gov/pubmed/30356705
http://dx.doi.org/10.3389/fphar.2018.01097
_version_ 1783363355860271104
author Zhang, Wei
Fan, Ying-Fang
Cai, Chao-Yun
Wang, Jing-Quan
Teng, Qiu-Xu
Lei, Zi-Ning
Zeng, Leli
Gupta, Pranav
Chen, Zhe-Sheng
author_facet Zhang, Wei
Fan, Ying-Fang
Cai, Chao-Yun
Wang, Jing-Quan
Teng, Qiu-Xu
Lei, Zi-Ning
Zeng, Leli
Gupta, Pranav
Chen, Zhe-Sheng
author_sort Zhang, Wei
collection PubMed
description The main characteristic of tumor cell resistance is multidrug resistance (MDR). MDR is the principle cause of the decline in clinical efficacy of chemotherapeutic drugs. There are several mechanisms that could cause MDR. Among these, one of the most important mechanisms underlying MDR is the overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) super-family of transporters, which effectively pump out cytotoxic agents and targeted anticancer drugs across the cell membrane. In recent years, studies found that ABC transporters and tyrosine kinase inhibitors (TKIs) interact with each other. TKIs may behave as substrates or inhibitors depending on the expression of specific pumps, drug concentration, their affinity for the transporters and types of co-administered agents. Therefore, we performed in vitro experiments to observe whether olmutinib could reverse MDR in cancer cells overexpressing ABCB1, ABCG2, or ABCC1 transporters. The results showed that olmutinib at 3 μM significantly reversed drug resistance mediated by ABCG2, but not by ABCB1 and ABCC1, by antagonizing the drug efflux function in ABCG2-overexpressing cells. In addition, olmutinib at reversal concentration affected neither the protein expression level nor the localization of ABCG2. The results observed from the accumulation/efflux study of olmutinib showed that olmutinib reversed ABCG2-mediated MDR with an increasing intracellular drug accumulation due to inhibited drug efflux. We also had consistent results with the ATPase assay that olmutinib stimulated ATPase activity of ABCG2 up to 3.5-fold. Additionally, the molecular interaction between olmutinib and ABCG2 was identified by docking simulation. Olmutinib not only interacts directly with ABCG2 but also works as a competitive inhibitor of the transport protein. In conclusion, olmutinib could reverse ABCG2-mediated MDR. The reversal effect of olmutinib on ABCG2-mediated MDR cells is not due to ABCG2 expression or intracellular localization, but rather related to its interaction with ABCG2 protein resulting in drug efflux inhibition and ATPase stimulation.
format Online
Article
Text
id pubmed-6189370
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-61893702018-10-23 Olmutinib (BI1482694/HM61713), a Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Reverses ABCG2-Mediated Multidrug Resistance in Cancer Cells Zhang, Wei Fan, Ying-Fang Cai, Chao-Yun Wang, Jing-Quan Teng, Qiu-Xu Lei, Zi-Ning Zeng, Leli Gupta, Pranav Chen, Zhe-Sheng Front Pharmacol Pharmacology The main characteristic of tumor cell resistance is multidrug resistance (MDR). MDR is the principle cause of the decline in clinical efficacy of chemotherapeutic drugs. There are several mechanisms that could cause MDR. Among these, one of the most important mechanisms underlying MDR is the overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) super-family of transporters, which effectively pump out cytotoxic agents and targeted anticancer drugs across the cell membrane. In recent years, studies found that ABC transporters and tyrosine kinase inhibitors (TKIs) interact with each other. TKIs may behave as substrates or inhibitors depending on the expression of specific pumps, drug concentration, their affinity for the transporters and types of co-administered agents. Therefore, we performed in vitro experiments to observe whether olmutinib could reverse MDR in cancer cells overexpressing ABCB1, ABCG2, or ABCC1 transporters. The results showed that olmutinib at 3 μM significantly reversed drug resistance mediated by ABCG2, but not by ABCB1 and ABCC1, by antagonizing the drug efflux function in ABCG2-overexpressing cells. In addition, olmutinib at reversal concentration affected neither the protein expression level nor the localization of ABCG2. The results observed from the accumulation/efflux study of olmutinib showed that olmutinib reversed ABCG2-mediated MDR with an increasing intracellular drug accumulation due to inhibited drug efflux. We also had consistent results with the ATPase assay that olmutinib stimulated ATPase activity of ABCG2 up to 3.5-fold. Additionally, the molecular interaction between olmutinib and ABCG2 was identified by docking simulation. Olmutinib not only interacts directly with ABCG2 but also works as a competitive inhibitor of the transport protein. In conclusion, olmutinib could reverse ABCG2-mediated MDR. The reversal effect of olmutinib on ABCG2-mediated MDR cells is not due to ABCG2 expression or intracellular localization, but rather related to its interaction with ABCG2 protein resulting in drug efflux inhibition and ATPase stimulation. Frontiers Media S.A. 2018-10-09 /pmc/articles/PMC6189370/ /pubmed/30356705 http://dx.doi.org/10.3389/fphar.2018.01097 Text en Copyright © 2018 Zhang, Fan, Cai, Wang, Teng, Lei, Zeng, Gupta and Chen. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zhang, Wei
Fan, Ying-Fang
Cai, Chao-Yun
Wang, Jing-Quan
Teng, Qiu-Xu
Lei, Zi-Ning
Zeng, Leli
Gupta, Pranav
Chen, Zhe-Sheng
Olmutinib (BI1482694/HM61713), a Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Reverses ABCG2-Mediated Multidrug Resistance in Cancer Cells
title Olmutinib (BI1482694/HM61713), a Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Reverses ABCG2-Mediated Multidrug Resistance in Cancer Cells
title_full Olmutinib (BI1482694/HM61713), a Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Reverses ABCG2-Mediated Multidrug Resistance in Cancer Cells
title_fullStr Olmutinib (BI1482694/HM61713), a Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Reverses ABCG2-Mediated Multidrug Resistance in Cancer Cells
title_full_unstemmed Olmutinib (BI1482694/HM61713), a Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Reverses ABCG2-Mediated Multidrug Resistance in Cancer Cells
title_short Olmutinib (BI1482694/HM61713), a Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Reverses ABCG2-Mediated Multidrug Resistance in Cancer Cells
title_sort olmutinib (bi1482694/hm61713), a novel epidermal growth factor receptor tyrosine kinase inhibitor, reverses abcg2-mediated multidrug resistance in cancer cells
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189370/
https://www.ncbi.nlm.nih.gov/pubmed/30356705
http://dx.doi.org/10.3389/fphar.2018.01097
work_keys_str_mv AT zhangwei olmutinibbi1482694hm61713anovelepidermalgrowthfactorreceptortyrosinekinaseinhibitorreversesabcg2mediatedmultidrugresistanceincancercells
AT fanyingfang olmutinibbi1482694hm61713anovelepidermalgrowthfactorreceptortyrosinekinaseinhibitorreversesabcg2mediatedmultidrugresistanceincancercells
AT caichaoyun olmutinibbi1482694hm61713anovelepidermalgrowthfactorreceptortyrosinekinaseinhibitorreversesabcg2mediatedmultidrugresistanceincancercells
AT wangjingquan olmutinibbi1482694hm61713anovelepidermalgrowthfactorreceptortyrosinekinaseinhibitorreversesabcg2mediatedmultidrugresistanceincancercells
AT tengqiuxu olmutinibbi1482694hm61713anovelepidermalgrowthfactorreceptortyrosinekinaseinhibitorreversesabcg2mediatedmultidrugresistanceincancercells
AT leizining olmutinibbi1482694hm61713anovelepidermalgrowthfactorreceptortyrosinekinaseinhibitorreversesabcg2mediatedmultidrugresistanceincancercells
AT zengleli olmutinibbi1482694hm61713anovelepidermalgrowthfactorreceptortyrosinekinaseinhibitorreversesabcg2mediatedmultidrugresistanceincancercells
AT guptapranav olmutinibbi1482694hm61713anovelepidermalgrowthfactorreceptortyrosinekinaseinhibitorreversesabcg2mediatedmultidrugresistanceincancercells
AT chenzhesheng olmutinibbi1482694hm61713anovelepidermalgrowthfactorreceptortyrosinekinaseinhibitorreversesabcg2mediatedmultidrugresistanceincancercells