Journal
FRONTIERS IN PHARMACOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.620874
Keywords
TOPK inhibitor; OTS964; ABCG2; ABC transporter; cancer
Categories
Funding
- Intramural Research Program of National Institutes of Health, National Cancer Institute, Center for Cancer Research
- Department of Pharmaceutical Sciences, St. John's University
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OTS964 is a potent inhibitor of TOPK that interacts with ABCG2 to affect multidrug resistance, and has an upregulating effect on ABCG2 transporter. It enhances resistance to ABCG2 substrate-drugs by inhibiting efflux function mediated by ABCG2.
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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