期刊
MOLECULAR CANCER
卷 21, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12943-022-01512-0
关键词
T-LAK cell-originated protein kinase (TOPK); PDZ-binding kinase (PBK); OTS964; ATP-binding cassette sub-family B member 1 (ABCB1); Multidrug resistance (MDR)
资金
- Department of Pharmaceutical Sciences, St. John's University
- National Natural Science Foundation of China [81872901]
- Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research
Overexpression of ABCBC1 significantly reduces sensitivity to OTS964 in cells and tumors, which can be antagonized by verapamil. OTS964 also induces resistance to other ABCBC1 substrate-drugs by stimulating ATPase activity and upregulating ABCBC1 expression levels, with comparable affinity to the substrate-binding site of human ABCBC1 protein.
Highlights ABCB1 overexpression significantly desensitized both drug-selected and gene-transfected cells, which overexpress ABCB1, to OTS964 and that this drug resistance can be antagonized by verapamil, a known ABCB1 inhibitor. Consistently, a similar trend was observed in tumor-bearing mice. OTS964 stimulated ATPase activity of ABCB1 and upregulated expression levels of ABCB1, resulting in induced resistance to other ABCB1 substrate-drugs, such as paclitaxel. OTS964 received a comparable affinity score and can dock into the substrate-binding site of human ABCB1 protein.
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