Triptonide stabilizes BIM to enhance oxaliplatin-induced ferroptosis and apoptosis in colorectal cancer.

Abstract

Oxaliplatin (OXA) is a common chemotherapeutic agent for advanced colorectal cancer. However, its effectiveness is limited by drug resistance, highlighting the need for combination therapies. In this study, Triptonide (TN), a diterpenoid compound is used to enhance the sensitivity of OXA, and the underlying mechanisms are investigated. Our findings indicated the combination of TN and OXA demonstrated strong synergistic anti-tumor effects across a broad concentration range in both HCT116 and LoVo cell lines, particularly at ratios ranging from 1:312 to 1:156. The combination of TN and OXA at low doses effectively inhibits growth and induces cell death in HCT116 and LoVo cells. TN and OXA cotreatment causes severe mitochondrial damage in colorectal cancer cells, leading to intracellular reactive oxygen species (ROS) accumulation, which subsequently triggers apoptosis and ferroptosis. Mechanistically, TN directly binds to BIM, a pro-apoptotic and ferroptotic protein, and stabilizes it. TN treatment led to increased expression of BIM and knockdown of BIM alleviated the growth inhibition of OXA in colorectal cancer cells. Finally, TN and OXA cotreatment significantly reduced the tumor weight and volume of LoVo-bearing nude mice in vivo. Taken together, our findings indicate that TN may serve as a novel therapeutic agent to enhance the efficacy OXA in the treatment of colorectal cancer.