Issue 22, 2024

Clinically used drug arsenic trioxide targets XIAP and overcomes apoptosis resistance in an organoid-based preclinical cancer model

Abstract

Drug resistance in tumor cells remains a persistent clinical challenge in the pursuit of effective anticancer therapy. XIAP, a member of the inhibitor of apoptosis protein (IAP) family, suppresses apoptosis via its Baculovirus IAP Repeat (BIR) domains and is responsible for drug resistance in various human cancers. Therefore, XIAP has attracted significant attention as a potential therapeutic target. However, no XIAP inhibitor is available for clinical use to date. In this study, we surprisingly observed that arsenic trioxide (ATO) induced a rapid depletion of XIAP in different cancer cells. Mechanistic studies revealed that arsenic attacked the cysteine residues of BIR domains and directly bound to XIAP, resulting in the release of zinc ions from this protein. Arsenic-XIAP binding suppressed the normal anti-apoptosis functions of BIR domains, and led to the ubiquitination-dependent degradation of XIAP. Importantly, we further demonstrate that arsenic sensitized a variety of apoptosis-resistant cancer cells, including patient-derived colon cancer organoids, to the chemotherapy drug using cisplatin as a showcase. These findings suggest that targeting XIAP with ATO offers an attractive strategy for combating apoptosis-resistant cancers in clinical practice.

Graphical abstract: Clinically used drug arsenic trioxide targets XIAP and overcomes apoptosis resistance in an organoid-based preclinical cancer model

Supplementary files

Article information

Article type
Edge Article
Submitted
24 2 2024
Accepted
29 4 2024
First published
03 5 2024
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2024,15, 8311-8322

Clinically used drug arsenic trioxide targets XIAP and overcomes apoptosis resistance in an organoid-based preclinical cancer model

L. Shi, J. Lu, X. Xia, X. Liu, H. Li, X. Li, J. Zhu, X. Li, H. Sun and X. Yang, Chem. Sci., 2024, 15, 8311 DOI: 10.1039/D4SC01294A

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