Proteasome inhibitor, ixazomib prevents topoisomerase-I degradation and reverses irinotecan resistance in colorectal cancer.

Abstract

Irinotecan, a topoisomerase I (topoI) inhibitor, is widely used for colorectal cancer, but resistance remains a major clinical challenge. We previously showed that camptothecin induces ubiquitin-proteasome pathway (UPP)-mediated topoI degradation. In this study, we investigated whether inhibition of UPP could prevent topoI degradation and restore camptothecin sensitivity. SN-38, an active metabolite of irinotecan, induced topoI degradation in irinotecan-resistant colorectal cancer cell lines, which was suppressed by ixazomib. The combination significantly enhanced cytotoxicity, colony inhibition, and reduced IC₅₀ values compared with SN-38 alone. Mechanistically, ixazomib prevented proteasome-mediated degradation of ubiquitinated topoI, restoring its stability. In vivo, the combination significantly suppressed tumor growth in a DLD-1 xenograft model compared with SN-38 alone. These findings indicate that UPP-dependent topoI degradation is a key mechanism underlying irinotecan resistance in colorectal cancer. Pharmacological inhibition of the proteasome effectively prevents topoI loss and restores irinotecan sensitivity, suggesting that proteasome inhibitors such as ixazomib may serve as promising therapeutic partners for camptothecin-based chemotherapy.