Curculigoside exhibits multiple therapeutic efficacy to induce apoptosis and ferroptosis in osteosarcoma via modulation of ROS and tumor microenvironment

Objective: Patients with osteosarcoma (OS) exhibit metastasis upon diagnosis, and the condition frequently acquires resistance to traditional chemotherapy treatments, failing the therapy. The objective of this research was to examine the impact of curculigoside (Cur), a key phenolic compound discovered in the rhizome of C. orchioides Gaertn, on OS cells and the surrounding tumor environment.

Methods: We assessed the impact of curculigoside on tumor inhibition in four osteosarcoma cell lines and mice tumor xenograft models using various techniques including cell viability assay, wound healing assay, cell Apoptosis analysis, immunofluorescent staining, and IHC. Moreover, we created a mini-PDX model by utilizing freshly obtained primary OS cells from surgically removed OS tissues to evaluate the possible clinical use of Cur.

Result: The results of our study show that Cur triggers cell death in OS cells and enhances the maturation of RAW264.7 cells. By effectively inhibiting the growth of OS cells, these actions mechanistically trigger the catastrophic buildup of unbound iron and uncontrolled lipid peroxidation, ultimately resulting in Ferroptosis. Moreover, additional validation of Cur's substantial antineoplastic impact is obtained through in vivo experiments employing xenograft and mini-PDX models.

Conclusions: To sum up, this research is the initial one to exhibit the anti-tumor effects of Cur on OS using various methods, indicating that Cur shows potential as a viable approach for treating OS.

Curculigoside; Ferroptosis; Lipotoxicity; Natural products; Osteosarcoma; Tumor-associated macrophages; iNOS.