The Novel Elemene Derivative, OMe-Ph-Elemene, Attenuates Oxidative Phosphorylation and Facilitates Apoptosis by Inducing Intracellular Reactive Oxygen Species

Abstract

The incidence and mortality rates of colorectal cancer have been steadily increasing, making it one of the most prevalent cancers globally. Although current chemotherapy drugs have shown some efficacy in treating this disease, their associated side effects necessitate the development of more effective treatments and medications. The clinical application of elemene is widely utilized in tumor treatment; however, its efficacy is hindered by the requirement for high dosage and suboptimal anticancer effects. Thus, we have made modifications and enhancements to elemene, resulting in the development of a novel compound named (E)-8-(3,4,5-OMe-Ph)-β-Elemene (abbreviated as OMe-Ph-Elemene) that demonstrates significantly enhanced efficacy in suppressing colorectal cancer. We conducted an in vivo study and demonstrated the potential of OMe-Ph-Elemene in suppressing the growth of colorectal cancer xenograft tumors in zebrafish. The in vitro experiments revealed that OMe-Ph-Elemene effectively inhibited the proliferation and migration of colorectal cancer SW480 and HT-29 cells by inducing reactive oxygen species (ROS)-caused apoptosis and inhibiting mitochondrial oxidative phosphorylation. The mechanism was elucidated through high-throughput proteomic analysis and molecular biological analysis, revealing that OMe-Ph-Elemene induced cellular oxidative stress by downregulating CISD3 and promoted cell apoptosis by downregulating TRIAP1 and upregulating HMOX1. Furthermore, OMe-Ph-Elemene suppressed colorectal cancer cells’ mitochondrial oxidative phosphorylation by downregulating NDUFA7. In summary, the utilization of the elemene parent nucleus structure has led to the derivation of a novel tumor suppressor compound characterized by high efficacy and low toxicity, thereby providing a significant reference for the development of innovative drugs for colorectal cancer treatment.

Keywords

• Elemene
• colorectal cancer
• oxidative stress
• oxidative phosphorylation
• apoptosis