Synergistic effects of dihydroartemisinin and cisplatin on inducing ferroptosis in gastric cancer through GPX4 inhibition.

Background: In the past several decades, cisplatin (DDP), in combination with other drugs, has been used as the mainstay chemotherapy drug for the treatment of gastric cancer (GC). However, the clinical application of DDP is restricted because of its toxic side effects, it is imperative to explore less toxic and more effective treatment strategies. Dihydroartemisinin (DHA) has been shown to exert potent anticancer effects through ferroptosis in multiple malignancies and has shown high efficacy and safety.

Methods: Cell viability assay, live/dead staining assay, EDU proliferation assay, MitoTracker assay, BODIPY C11 assay and other cell assays in vitro were employed to observe DHA in combination with DDP inducing ferroptosis in GC. Subsequently, proteomic analysis integrated with database analysis and clinical sample detection were utilized to elucidate the mechanism of DHA inducing ferroptosis in GC both in vitro and in vivo.

Results: In this study, we found that DHA combined with DDP can synergistically inhibit the proliferation, invasion and migration of GC cells and induce ferroptosis. Further studies have shown that DHA acts in combination with DDP to induce ferroptosis in GC cells by inhibiting GPX4 in vivo and in vitro.

Conclusion: In summary, this study is the first to report that DHA and DDP synergically promote ferroptosis in GC cells, the combination of DDP and DHA is a promising strategy from the perspective of toxicity of DDP, which may be a promising therapeutic approach.