Polyphyllin VII Enhances the Antitumor Activity of Cisplatin in Non‐Small Cell Lung Cancer Cells by Inducing Ferroptosis and Enhancing Apoptosis

Cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC) is a common cause of treatment failure and a significant contributor to increased mortality. To tackle this issue, the integration of traditional Chinese medicine with chemotherapy has been proposed as a promising approach. The potential synergistic effect of combining polyphyllin VII (PPVII) and DDP in overcoming DDP resistance in NSCLC cells has not been thoroughly investigated yet. In this study, H1299 cells were exposed to gradient concentrations of PPVII and DDP to determine their 50% inhibitory concentration values, and the most effective concentration was applied in subsequent experiments. The combination of PPVII and DDP was evaluated for its effects on H1299 cell proliferation, apoptosis, viability, and the expression of proteins linked to apoptosis and ferroptosis. To further elucidate the underlying mechanisms, the impact of the combination on DNA damage in H1299 cells was also examined. Our results demonstrated that PPVII significantly potentiated the antitumor effects of DDP in H1299 cells in a dose-dependent manner (p < 0.05). Furthermore, PPVII was observed to work synergistically with DDP to suppress proliferation and promote apoptosis in H1299 cells (p < 0.05). Western blotting analysis proved that the combination treatment upregulated proapoptotic proteins (B-cell lymphoma 2-associated X protein, cleaved-caspase 3 and cleaved-PARP), downregulated antiapoptotic protein (Bcl-2), and promoted ferroptosis-associated proteins (long-chain acyl-coenzyme A synthase 4 and NADPH oxidase 4) as well as DNA damage-associated protein (γH2AX) (p < 0.05). Overall, the combination of PPVII and DDP significantly enhanced antitumor activity in H1299 cells through the modulation of DNA damage and ferroptosis, suggesting its potential as an effective therapeutic approach against DDP-resistant NSCLC.