Platycodin D sensitizes head and neck squamous cell carcinoma to cisplatin by inducing autophagy arrest

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies worldwide. Cisplatin, a widely used chemotherapeutic agent, exerts its anticancer effect by inducing DNA damage, and inhibiting transcription and replication. However, its repeated administration can lead to severe side effects and the development of drug resistance, thereby limiting its clinical efficacy. Thus, novel combination strategies are urgently needed to enhance the anticancer effects of cisplatin. The present study aimed to investigate the potential of Platycodin D (PD), a natural saponin extracted from <i>Platycodon grandiflorus</i>, to enhance cisplatin sensitivity in HNSCC cells. The results demonstrated that combination treatment with PD and cisplatin synergistically reduced cell viability and markedly suppressed colony formation compared with either agent alone. Furthermore, the combination treatment markedly increased intracellular reactive oxygen species (ROS) levels, and markedly downregulated the expression levels of antioxidant genes, including heme oxygenase‑1, NAD(P)H quinone dehydrogenase 1, superoxide dismutase 1 and sulfiredoxin 1. Additionally, the combination treatment excessively activated autophagy, whereas PD inhibited autophagic flux, as determined by LC3A/B and p62 accumulation following Bafilomycin A1 treatment, ultimately promoting apoptosis. These findings suggested that PD may serve as a potential cisplatin sensitizer by enhancing ROS accumulation and disrupting autophagy, thereby presenting a promising combination therapeutic strategy for the treatment of HNSCC.