SeSA-HCPT: A dual-targeting agent that induces DNA damage and inhibits repair for castration-resistant prostate cancer therapy.

Castration-resistant prostate cancer (CRPC) remains difficult to treat due to tumor heterogeneity and resistance. We developed SeSA-HCPT, a dual-targeting compound that links the topoisomerase I inhibitor hydroxycamptothecin (HCPT) with a selenium analog of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid. SeSA-HCPT showed markedly higher cytotoxicity in prostate cancer (PCa) cells than single or combined treatments, while sparing normal keratinocytes. At effective concentrations, it triggered pronounced S-phase arrest and apoptosis, driven by Topo I inhibition and extensive DNA double-strand breaks; concurrently, SeSA-HCPT suppressed homologous recombination through downregulation of KIF4A and impaired RAD51 recruitment. In a PC-3 xenograft model, SeSA-HCPT significantly inhibited tumor growth relative to the combination treatment without observable systemic toxicity. These results nominate SeSA-HCPT as a promising dual-mechanism therapeutic candidate for advanced PCa.