Evodiamine induces reactive oxygen species-dependent apoptosis and necroptosis in human melanoma A-375 cells

Melanoma is a common solid malignant tumor with a high frequency of metastasis and relapse. Evodiamine (EVO), a natural small molecule, has recently attracted considerable attention due to its pharmacological action, including its Anticancer effects. However, the mechanism of the cytotoxic effect exerted by EVO on tumor cells is not yet fully understood. The present study aimed to evaluate the antitumor effects of evodiamine in human melanoma A-375 cells. The results demonstrated that EVO inhibited cell proliferation and induced cell cycle arrest at the G₂/M stage in human melanoma A-375 cells. The results also revealed that EVO exposure induced the activation of Caspase-3, caspase-9 and poly (ADP-ribose) polymerase 1, as well as mitochondrial membrane potential dissipation in a time-dependent manner, indicating that EVO induced intrinsic Apoptosis in A-375 cells. Furthermore, the results revealed that receptor-interacting serine/threonine kinase (RIP) and RIP3 were sequentially activated, suggesting that Necroptosis may also be involved in EVO-induced cell death in A-375 cells. In addition, co-treatment with catalase was demonstrated to significantly attenuate the EVO-induced cell death in A-375 cells, indicating that Reactive Oxygen Species (ROS) may serve an important role in EVO-induced cell death. In conclusion, the results of the present study unveiled a novel mechanism of drug action by EVO in human melanoma cells and suggested its potential value in treating human melanoma by inducing cell death via ROS activation.