Toosendanin-induced apoptosis in colorectal cancer cells is associated with the κ-opioid receptor/β-catenin signaling axis

Developing new drugs for killing colorectal cancer (CRC) cells is urgently needed. Here, we explored the antitumor effects of toosendanin (TSN) in CRC, as well as explored its antitumor mechanisms and direct targets. Cell proliferation and apoptosis were analyzed by CCK8, colony formation, real-time cell impedance and flow cytometry. The signaling pathway and Wnt activity were analyzed by Wnt luciferase activity assay, quantitative real-time PCR and western blot. The interaction between TSN and the kappa-opioid receptor was analyzed by a molecular docking simulation. BALB/c nude mice were used to detect the effects of TSN on tumor growth in vivo. We found that TSN inhibited proliferation, induced GI phase arrest and caused caspase-dependent apoptosis in both 5-FU-sensitive and 5-FU-resistant CRC cells. Moreover, TSN effectively inhibited CRC growth in vivo. In terms of the mechanism, TSN inhibited Wnt/beta-catenin signaling in CRC cells, and the molecular docking results showed that TSN could bind to kappa-opioid receptors directly. Additionally, TSN-induced apoptosis and beta-catenin decline were both reversed by the selective kappa-opioid receptor agonist U50,488H. Our data demonstrate that TSN-induced apoptosis in CRC cells is associated with the kappa-opioid receptor/beta-catenin signaling axis, and TSN has promising potential as an antitumor agent for CRC treatment.