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Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells

One pivotal factor that leads to multidrug resistance (MDR) is the overexpression of ABCG2. Therefore, tremendous effort has been devoted to the search of effective reversal agents to overcome ABCG2‐mediated MDR. CC‐671 is a potent and selective inhibitor of both TTK (human protein kinase monopolar...

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Autores principales: Wu, Zhuo‐Xun, Yang, Yuqi, Wang, Guangsuo, Wang, Jing‐Quan, Teng, Qiu‐Xu, Sun, Lingling, Lei, Zi‐Ning, Lin, Lizhu, Chen, Zhe‐Sheng, Zou, Chang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419038/
https://www.ncbi.nlm.nih.gov/pubmed/32478948
http://dx.doi.org/10.1111/cas.14505
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author Wu, Zhuo‐Xun
Yang, Yuqi
Wang, Guangsuo
Wang, Jing‐Quan
Teng, Qiu‐Xu
Sun, Lingling
Lei, Zi‐Ning
Lin, Lizhu
Chen, Zhe‐Sheng
Zou, Chang
author_facet Wu, Zhuo‐Xun
Yang, Yuqi
Wang, Guangsuo
Wang, Jing‐Quan
Teng, Qiu‐Xu
Sun, Lingling
Lei, Zi‐Ning
Lin, Lizhu
Chen, Zhe‐Sheng
Zou, Chang
author_sort Wu, Zhuo‐Xun
collection PubMed
description One pivotal factor that leads to multidrug resistance (MDR) is the overexpression of ABCG2. Therefore, tremendous effort has been devoted to the search of effective reversal agents to overcome ABCG2‐mediated MDR. CC‐671 is a potent and selective inhibitor of both TTK (human protein kinase monopolar spindle 1 [hMps1]) and CDC like kinase 2 (CLK2). It represents a new class of cancer therapeutic drugs. In this study, we show that CC‐671 is an effective ABCG2 reversal agent that enhances the efficacy of chemotherapeutic drugs in ABCG2‐overexpressing lung cancer cells. Mechanistic studies show that the reversal effect of CC‐671 is primarily attributed to the inhibition of the drug efflux activity of ABCG2, which leads to an increased intracellular level of chemotherapeutic drugs. In addition, CC‐671 does not alter the protein expression or subcellular localization of ABCG2. The computational molecule docking analysis suggests CC‐671 has high binding affinity to the drug‐binding site of ABCG2. In conclusion, we reveal the interaction between CC‐671 and ABCG2, providing a rationale for the potential combined use of CC‐671 with ABCG2 substrate to overcome MDR.
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spelling pubmed-74190382020-08-12 Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells Wu, Zhuo‐Xun Yang, Yuqi Wang, Guangsuo Wang, Jing‐Quan Teng, Qiu‐Xu Sun, Lingling Lei, Zi‐Ning Lin, Lizhu Chen, Zhe‐Sheng Zou, Chang Cancer Sci Original Articles One pivotal factor that leads to multidrug resistance (MDR) is the overexpression of ABCG2. Therefore, tremendous effort has been devoted to the search of effective reversal agents to overcome ABCG2‐mediated MDR. CC‐671 is a potent and selective inhibitor of both TTK (human protein kinase monopolar spindle 1 [hMps1]) and CDC like kinase 2 (CLK2). It represents a new class of cancer therapeutic drugs. In this study, we show that CC‐671 is an effective ABCG2 reversal agent that enhances the efficacy of chemotherapeutic drugs in ABCG2‐overexpressing lung cancer cells. Mechanistic studies show that the reversal effect of CC‐671 is primarily attributed to the inhibition of the drug efflux activity of ABCG2, which leads to an increased intracellular level of chemotherapeutic drugs. In addition, CC‐671 does not alter the protein expression or subcellular localization of ABCG2. The computational molecule docking analysis suggests CC‐671 has high binding affinity to the drug‐binding site of ABCG2. In conclusion, we reveal the interaction between CC‐671 and ABCG2, providing a rationale for the potential combined use of CC‐671 with ABCG2 substrate to overcome MDR. John Wiley and Sons Inc. 2020-06-29 2020-08 /pmc/articles/PMC7419038/ /pubmed/32478948 http://dx.doi.org/10.1111/cas.14505 Text en © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Wu, Zhuo‐Xun
Yang, Yuqi
Wang, Guangsuo
Wang, Jing‐Quan
Teng, Qiu‐Xu
Sun, Lingling
Lei, Zi‐Ning
Lin, Lizhu
Chen, Zhe‐Sheng
Zou, Chang
Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells
title Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells
title_full Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells
title_fullStr Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells
title_full_unstemmed Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells
title_short Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells
title_sort dual ttk/clk2 inhibitor, cc‐671, selectively antagonizes abcg2‐mediated multidrug resistance in lung cancer cells
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419038/
https://www.ncbi.nlm.nih.gov/pubmed/32478948
http://dx.doi.org/10.1111/cas.14505
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