Selamectin increases cisplatin sensitivity by inhibiting cisplatin-resistant genes expression and autophagy in uveal melanoma

Cisplatin resistance is the main reason for uveal melanoma (UM) treatment failure. Thus, developing strategy that increasing cisplatin sensitivity is needed. In this study, we performed drug repositioning analysis with the Connectivity Map database using a panel of previously identified cisplatin sensitivity -associated genes and cisplatin resistance-associated genes as the signature and obtained the anti -parasitic drug selamectin. We demonstrated that the selamectin and cisplatin combination showed a synergistic effect on inhibiting UM cell growth. Experiments in tumor-bearing nude mice further showed that selamectin and cisplatin have synergistic effects in reducing tumor growth. Previous studies have linked increased autophagy with tumor resistance to chemotherapy. We found that selamectin inhibited the expression of the autophagy-related gene ATG9B, thus reducing autophagy. The cisplatin resistance -associated genes PDGFRB, DUSP1, MAST1 and IL11 were significantly downregulated in UM cells treated with selamectin. In summary, our study shows that selamectin enhanced the sensitivity of UM to cisplatin, through the mechanism of inhibiting cisplatin resistance-associated gene expression and autophagy. These findings may provide a new strategy for the treatment of UM.(c) 2023 Elsevier Inc. All rights reserved.

Automated summary

In this study, the anti-parasitic drug selamectin was identified through drug repositioning analysis as a potential agent to enhance the sensitivity of uveal melanoma (UM) cells to cisplatin. The combination of selamectin and cisplatin showed a synergistic effect in inhibiting UM cell growth and reducing tumor growth in mice. Selamectin achieved these effects by inhibiting autophagy and downregulating cisplatin resistance-associated genes.