4.7 Article

PBK/TOPK inhibitor OTS964 resistance is mediated by ABCB1-dependent transport function in cancer: in vitro and in vivo study

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

  1. Department of Pharmaceutical Sciences, St. John's University
  2. National Natural Science Foundation of China [81872901]
  3. Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research

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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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