IMR Press / FBL / Volume 27 / Issue 1 / DOI: 10.31083/j.fbl2701005
Open Access Original Research
ABCB1 limits the cytotoxic activity of TAK-243, an inhibitor of the ubiquitin-activating enzyme UBA1
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1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
2 Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
3 Department of Reproductive Medicine, Wuxi People's Hospital Affiliated to Nanjing Medical University, 214023 Wuxi, Jiangsu, China
*Correspondence: chenz@stjohns.edu (Zhesheng Chen); pingfengfeng2017@njmu.edu.cn (Fengfeng Ping)
Academic Editor: Graham Pawelec
Front. Biosci. (Landmark Ed) 2022, 27(1), 5; https://doi.org/10.31083/j.fbl2701005
Submitted: 25 September 2021 | Revised: 20 November 2021 | Accepted: 24 November 2021 | Published: 5 January 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

Background: One of the major concerns of cancer therapy is the emergence of multidrug resistance (MDR). The MDR-associated ATP-binding cassette sub-family B member 1 (ABCB1) transporter is established to mediate resistance against numerous anticancer drugs. In this study, we demonstrated that the Ubiquitin-like modifier activating enzyme 1 (UBA1) inhibitor TAK-243 is transported by the ABCB1. Methods: MTT assay was performed to evaluate the cytotoxicity of TAK-243. Western blot was carried out to investigate if TAK-243 affect to ABCB1 protein expression in cancer cells. High Performance Liquid Chromatography (HPLC) and ATPase assay were carried out to confirm TAK-243 as an ABCB1 substrate. [3H]-paclitaxel accumulation assay was used to determine the MDR reversal effect of TAK-243. Computational docking analysis was performed to investigate the drug-transporter binding position. Results: The cytotoxicity profile showed that TAK-243 was less effective in ABCB1-overexpressing cells than in the parental cells, but pharmacological inhibition or knockout the gene of ABCB1 was able to reverse TAK-243 resistance. Furthermore, TAK-243 potently stimulated ABCB1 ATPase activity and the HPLC analysis revealed that TAK-243 accumulation was significantly reduced in ABCB1-overexpressing cells. Finally, the computational docking analysis indicates a high binding affinity between TAK-243 and human ABCB1 transporter. Conclusions: Our in vitro data characterized TAK-243 as a substrate of ABCB1, which may predict limited anticancer effect of this compound in drug resistant tumors.

Keywords
Ubiquitin-activating enzyme
TAK-243
Multidrug resistance
ABCB1
In vitro cytotoxicity
Figures
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