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

Authors :
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
Source :
Cancer Science; Aug2020, Vol. 111 Issue 8, p2872-2882, 11p
Publication Year :
2020

Abstract

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
13479032
Volume :
111
Issue :
8
Database :
Complementary Index
Journal :
Cancer Science
Publication Type :
Academic Journal
Accession number :
145051437
Full Text :
https://doi.org/10.1111/cas.14505