Diosmetin overcomes resistance to cisplatin in ovarian cancer by suppressing the MAPK signaling pathway.

Cisplatin (DDP) is a widely used chemotherapeutic agent for ovarian cancer (OC) therapy. However, the adverse effects and frequent resistance to DDP make its therapeutic efficacy suboptimal. Combination treatment with an agent capable of overcoming DDP resistance may be a promising solution. Here, we conducted a drug library screen for agents that increase DDP efficiency in a trained DDP-resistant OC cell line (SKOV3/DDP). Diosmetin (Dio), a natural flavonoid abundant in olive leaves and citrus fruits, was identified to synergize with DDP to reduce OC cell growth through apoptosis both in vitro and in vivo, as evidenced by increased expression of the proapoptotic proteins Cleaved-Caspase3 and Cleaved-PARP, as well as decreased expression of the antiapoptotic protein BCL-2 in SKOV3/DDP cells. Mechanistically, compared with Dio or DDP treatment alone, combined Dio and DDP treatment suppressed the MAPK signaling pathway, represented by reduced phosphorylation of JNK, ERK, and P38. These findings demonstrated that Dio potentiates the anticancer effects of DDP both in vitro and in vivo, indicating that Dio is a promising adjuvant for OC treatment.