Effects of luteolin on canine osteosarcoma: Suppression of cell proliferation and synergy with cisplatin

Canine osteosarcoma is characterized by aggressiveness, easy metastasis to the lungs, and high mortality after standard therapy. Luteolin is a flavonoid found in vegetables and fruits and has diverse functions. Elucidation of the biological mechanisms of luteolin on canine osteosarcoma will enhance the efficacy of chemotherapeutic agents in canine tumors. In this study, we examined the effects of luteolin in the canine osteosarcoma cell lines, D17 and DSN. The results of this study show that luteolin inhibited canine osteosarcoma cell proliferation and induced apoptosis by altering cell-cycle proportion, producing reactive oxygen species, increasing the loss of mitochondrial membrane potential, and reducing cytosolic Ca²⁺ concentration. In addition, luteolin activated ERK1/2 and inactivated phosphoinositide 3-kinase/AKT signaling in canine osteosarcoma cells. Moreover, luteolin showed synergistic effects with cisplatin to reduce cell proliferation. In summary, luteolin induced cell death by initiating mitochondrial dysfunction and regulating intracellular signal transduction in canine osteosarcoma cells.