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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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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. |
format | Online Article Text |
id | pubmed-7419038 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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