ABSTRACT
Osteosarcoma, usually originating in the stroma, is the most common primary bone cancer in adolescents, and its prognosis is poor. Surgery, adjuvant and neoadjuvant chemotherapy and radiation therapy are not satisfactory at the present time. Therefore, it is critical to develop novel therapeutic strategies to improve the quality of life and long-term survival rate of osteosarcoma patients. In this study, we discovered that zoledronic acid (ZOL) dramatically increased cell death in osteosarcoma cells, and this cytotoxicity was greatly reversed by liproxstatin-1 (a ferroptosis inhibitor). ZOL also had an obvious effect on lipid peroxidation and reactive oxygen species (ROS), which suggested that ZOL most certainly induces ferroptosis in osteosarcoma cells. In addition, we further found that ZOL increases cytochrome P450 oxidoreductase (POR) expression dose dependently in osteosarcoma cell lines. Knockdown of POR attenuated ZOL-induced cytotoxicity and attenuated the effect of ferroptosis in osteosarcoma cells, which indicated that POR plays an important role in ferroptosis. Moreover, we also found that ZOL inhibits osteosarcoma growth in vivo. Our findings suggest that ZOL induces ferroptosis by upregulating POR expression to increase ROS levels and upregulate lipid peroxidation levels in osteosarcoma cells. POR may be used as a therapeutic target to inhibit osteosarcoma.
Subject(s)
Bone Neoplasms , Ferroptosis , Osteosarcoma , Humans , Bone Neoplasms/drug therapy , Cell Line, Tumor , Diphosphonates/pharmacology , Diphosphonates/therapeutic use , Imidazoles/pharmacology , Imidazoles/therapeutic use , Osteosarcoma/drug therapy , Quality of Life , Reactive Oxygen Species/metabolism , Zoledronic Acid/pharmacology , Zoledronic Acid/therapeutic useABSTRACT
Osteosarcoma is the most common malignant tumors of bone. Since 1970s, researchers had used chemotherapy drugs to treat osteosarcoma. However, multidrug resistance is a major adverse reaction that affects the efficacy of chemotherapy drugs, leading to the reduced survival rate of osteosarcoma patients. The Notch signaling pathway plays an important role in osteosarcoma proliferation, which affects tumor resistance by reducing intracellular drug accumulation, regulating epithelial-mesenchymal transition, dysregulating microRNA, disrupting the expression of apoptosis genes, and regulating tumor stem cells.
