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

Molecular Cancer

卷:21

Yuqi Yang¹  Qiu-Xu Teng¹  Jing-Quan Wang¹  Zi-Ning Lei¹  Ning Ji¹  Zhuo-Xun Wu¹  Zhe-Sheng Chen¹  Sabrina Lusvarghi²  Suresh V. Ambudkar² 

[1] Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University;

[2] Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH;

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);   

DOI  :  10.1186/s12943-022-01512-0

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown