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

Area of Science:

• Oncology
• Pharmacology
• Genetics

Background:

• Cisplatin resistance is a major challenge in uveal melanoma (UM) treatment, leading to therapeutic failure.
• Developing strategies to overcome cisplatin resistance is crucial for improving UM patient outcomes.

Purpose of the Study:

• To identify novel therapeutic strategies by repositioning existing drugs to enhance cisplatin sensitivity in UM.
• To investigate the synergistic effects of selamectin and cisplatin in UM treatment and elucidate the underlying mechanisms.

Main Methods:

• Drug repositioning analysis using the Connectivity Map database with UM-associated gene signatures.
• In vitro assessment of synergistic effects of selamectin and cisplatin on UM cell growth.
• In vivo efficacy studies in tumor-bearing nude mice.
• Analysis of autophagy-related gene expression (ATG9B) and cisplatin resistance-associated genes (PDGFRB, DUSP1, MAST1, IL11).

Main Results:

• Selamectin was identified as a potential drug to enhance cisplatin sensitivity in UM.
• The combination of selamectin and cisplatin demonstrated synergistic inhibition of UM cell growth and tumor progression in vivo.
• Selamectin treatment downregulated the expression of ATG9B, reducing autophagy, and also decreased cisplatin resistance-associated genes.

Conclusions:

• Selamectin enhances UM sensitivity to cisplatin through the inhibition of cisplatin resistance-associated gene expression and autophagy.
• The combination of selamectin and cisplatin presents a promising new therapeutic strategy for uveal melanoma treatment.