Polydatin-mediated shift in redox balance and its anti-cancer effects on osteosarcoma cells in vitro

Osteosarcoma (OS), the most common bone cancer in children and young adults, remains a significant therapeutic challenge due to high rates of metastasis and drug resistance. Polydatin (PD), a natural glucoside derivative of resveratrol, has shown promising anti-cancer activity, particularly through its regulation of oxidative stress, cell cycle arrest, and apoptosis induction. This study explores for the first time the redox-dependent anti-cancer effects of PD on SAOS-2 and U2OS cells. It investigates ROS modulation, glutathione (GSH) depletion, and ferroptosis markers, including total iron and intracellular malondialdehyde (MDA), using assay kits. The involvement of oxidative stress regulators such as SIRT1 and Nrf2 was also assessed through Western blot and real-time PCR analyses. Additionally, cell-based biochemical assays were employed to evaluate the efficacy of PD under tumor-like conditions of hypoxia and serum starvation.The study further examines PD’s potential as an adjuvant therapy for OS by assessing its synergistic effects on OS cell viability and proliferation when combined with ROS-inducing chemotherapeutic agents, doxorubicin (DOX) and cisplatin (CIS). My findings provide the first evidence that PD-induced redox imbalance is a critical mechanism underlying its anti-cancer activity in SAOS-2 and U2OS cells. By elevating intracellular ROS levels, depleting GSH and increasing intracellular levels of both total iron and MDA (markers of ferroptosis), PD sensitizes OS cells to oxidative stress-related cell death, making them more vulnerable to survival challenges, particularly under hypoxic conditions and drug treatments. Importantly, PD exhibited minimal toxicity to normal osteoblast cells (hFOB 1.19), suggesting a favorable therapeutic window. These results indicate that PD warrants further investigation to elucidate the precise molecular driving its pro-oxidant effects in OS.