PBK/TOPK inhibitor OTS964 resistance is mediated by ABCB1-dependent transport function in cancer: in vitro and in vivo study
Yuqi Yang, Qiu‐Xu Teng, Zhuo‐Xun Wu, Jing‐Quan Wang, Zi‐Ning Lei, Sabrina Lusvarghi, Suresh V. Ambudkar, Ning Ji, Zhe‐Sheng Chen
Abstract
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.
Topics & Concepts
In vivoBiologyIn vitroCancerFunction (biology)Cancer researchPharmacologyResistance (ecology)Cell biologyBiochemistryGeneticsEcologyDrug Transport and Resistance MechanismsFOXO transcription factor regulationTrace Elements in Health