Harmine exerts anticancer effects through the ROS/p38 axis to induce autophagy and apoptosis in osteosarcoma

Osteosarcomas are malignant bone tumors that occur primarily in adolescents, and are often associated with high rates of pulmonary metastasis and mortality. Harmine is a plant-derived β-carboline alkaloid with anti-inflammatory and antitumor activities. However, its therapeutic role in osteosarcoma remains unexplored. In this study, harmine exhibited dose- and time-dependent inhibition of osteosarcoma growth. Mechanistically, harmine increased the intracellular levels of reactive oxygen species (ROS) and induced phosphorylation of p38, which led to autophagy and apoptosis, as well as inhibition of osteosarcoma cell invasion and migration. Notably, treatment with an ROS scavenger and p38 inhibitor significantly weakened the harmine-induced autophagy and apoptosis. In vivo, harmine significantly reduced the volume and weight of tumor tissue in mice that received osteosarcoma xenografts. The expression of proliferating cell nuclear antigen (PCNA) was downregulated, and the expression of cleaved caspase-3, LC3BII/I, and phosphorylated p38 was upregulated in tumor tissues. Moreover, in mice that received osteosarcoma xenografts, harmine did not cause toxic. adverse reactions involving the major organs. These results suggest that harmine exerts an inhibitory effect on osteosarcoma by promoting ROS generation and phosphorylation of p38 which leads to autophagy and apoptosis.