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OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance

OTS964 is a potent T-LAK cell-originated protein kinase (TOPK) inhibitor. Herein, we investigated the interaction of OTS964 and multidrug resistance (MDR)-associated ATP-binding cassette sub-family G member 2 (ABCG2). The cell viability assay indicated that the effect of OTS964 is limited in cancer...

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Autores principales: Yang, Yuqi, Wu, Zhuo-Xun, Wang, Jing-Quan, Teng, Qiu-Xu, Lei, Zi-Ning, Lusvarghi, Sabrina, Ambudkar, Suresh V., Chen, Zhe-Sheng, Yang, Dong-Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917255/
https://www.ncbi.nlm.nih.gov/pubmed/33658942
http://dx.doi.org/10.3389/fphar.2021.620874
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author Yang, Yuqi
Wu, Zhuo-Xun
Wang, Jing-Quan
Teng, Qiu-Xu
Lei, Zi-Ning
Lusvarghi, Sabrina
Ambudkar, Suresh V.
Chen, Zhe-Sheng
Yang, Dong-Hua
author_facet Yang, Yuqi
Wu, Zhuo-Xun
Wang, Jing-Quan
Teng, Qiu-Xu
Lei, Zi-Ning
Lusvarghi, Sabrina
Ambudkar, Suresh V.
Chen, Zhe-Sheng
Yang, Dong-Hua
author_sort Yang, Yuqi
collection PubMed
description OTS964 is a potent T-LAK cell-originated protein kinase (TOPK) inhibitor. Herein, we investigated the interaction of OTS964 and multidrug resistance (MDR)-associated ATP-binding cassette sub-family G member 2 (ABCG2). The cell viability assay indicated that the effect of OTS964 is limited in cancer drug-resistant and transfected cells overexpressing ABCG2. We found that the known ABCG2 transporter inhibitor has the ability to sensitize ABCG2-overexpressing cells to OTS964. In mechanism-based studies, OTS964 shows inhibitory effect on the efflux function mediated by ABCG2, and in turn, affects the pharmacokinetic profile of other ABCG2 substrate-drugs. Furthermore, OTS964 upregulates ABCG2 protein expression, resulting in enhanced resistance to ABCG2 substrate-drugs. The ATPase assay demonstrated that OTS964 stimulates ATPase activity of ABCG2 in a concentration-dependent manner. The computational molecular docking analysis combined with results from ATPase assay suggested that OTS964 interacts with drug-binding pocket of ABCG2 and has substrate-like behaviors. Thus, OTS964 is an MDR-susceptible agent due to its interactions with ABCG2, and overexpression of ABCG2 transporter may attenuate its therapeutic effect in cancer cells.
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spelling pubmed-79172552021-03-02 OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance Yang, Yuqi Wu, Zhuo-Xun Wang, Jing-Quan Teng, Qiu-Xu Lei, Zi-Ning Lusvarghi, Sabrina Ambudkar, Suresh V. Chen, Zhe-Sheng Yang, Dong-Hua Front Pharmacol Pharmacology OTS964 is a potent T-LAK cell-originated protein kinase (TOPK) inhibitor. Herein, we investigated the interaction of OTS964 and multidrug resistance (MDR)-associated ATP-binding cassette sub-family G member 2 (ABCG2). The cell viability assay indicated that the effect of OTS964 is limited in cancer drug-resistant and transfected cells overexpressing ABCG2. We found that the known ABCG2 transporter inhibitor has the ability to sensitize ABCG2-overexpressing cells to OTS964. In mechanism-based studies, OTS964 shows inhibitory effect on the efflux function mediated by ABCG2, and in turn, affects the pharmacokinetic profile of other ABCG2 substrate-drugs. Furthermore, OTS964 upregulates ABCG2 protein expression, resulting in enhanced resistance to ABCG2 substrate-drugs. The ATPase assay demonstrated that OTS964 stimulates ATPase activity of ABCG2 in a concentration-dependent manner. The computational molecular docking analysis combined with results from ATPase assay suggested that OTS964 interacts with drug-binding pocket of ABCG2 and has substrate-like behaviors. Thus, OTS964 is an MDR-susceptible agent due to its interactions with ABCG2, and overexpression of ABCG2 transporter may attenuate its therapeutic effect in cancer cells. Frontiers Media S.A. 2021-02-15 /pmc/articles/PMC7917255/ /pubmed/33658942 http://dx.doi.org/10.3389/fphar.2021.620874 Text en Copyright © 2021 Yang, Wu, Wang, Teng, Lei, Lusvarghi, Ambudkar, Chen and Yang. 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) (http://creativecommons.org/licenses/by/4.0/) . 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
Yang, Yuqi
Wu, Zhuo-Xun
Wang, Jing-Quan
Teng, Qiu-Xu
Lei, Zi-Ning
Lusvarghi, Sabrina
Ambudkar, Suresh V.
Chen, Zhe-Sheng
Yang, Dong-Hua
OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance
title OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance
title_full OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance
title_fullStr OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance
title_full_unstemmed OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance
title_short OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance
title_sort ots964, a topk inhibitor, is susceptible to abcg2-mediated drug resistance
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917255/
https://www.ncbi.nlm.nih.gov/pubmed/33658942
http://dx.doi.org/10.3389/fphar.2021.620874
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