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

## TL;DR

SeSA-HCPT is a new drug that targets two pathways in prostate cancer cells, causing DNA damage and preventing repair, which could lead to better treatment for advanced prostate cancer.

## Contribution

SeSA-HCPT is a novel dual-targeting agent combining Topo I and HDAC inhibition for prostate cancer therapy.

## Key findings

- SeSA-HCPT showed higher cytotoxicity in prostate cancer cells than single or combined treatments.
- It induced DNA damage and S-phase arrest while suppressing homologous recombination repair.
- Oral SeSA-HCPT inhibited tumor growth in a xenograft model with minimal toxicity.

## Abstract

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.

•SeSA-HCPT is a dual-target inhibitor integrating Topo I and HDAC inhibition•SeSA-HCPT induces potent DNA damage and S-phase arrest in prostate cancer cells•SeSA-HCPT impairs homologous recombination by suppressing KIF4A-RAD51 signaling•Oral SeSA-HCPT markedly inhibits CRPC tumor growth with minimal systemic toxicity

SeSA-HCPT is a dual-target inhibitor integrating Topo I and HDAC inhibition

SeSA-HCPT induces potent DNA damage and S-phase arrest in prostate cancer cells

SeSA-HCPT impairs homologous recombination by suppressing KIF4A-RAD51 signaling

Oral SeSA-HCPT markedly inhibits CRPC tumor growth with minimal systemic toxicity

Molecular biology; Biotechnology; Cancer