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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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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. |
format | Online Article Text |
id | pubmed-7917255 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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