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

  • iScience. 2026 Jan 29;29(2):114824. doi: 10.1016/j.isci.2026.114824.
Yajie Wang  1 ,  Qiuyu Wang  1 ,  Li Meng  2 ,  Xiaoying Lian  1 ,  Xinyue Wu  1 ,  Yuqing Wang  1 ,  Tianyu Zhang  1 ,  ShiLin Wei  1 ,  Yanming Wang  2 ,  Changjun Zhu  2
Affiliations
  • 1. Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University, Tianjin 300387, China.
  • 2. College of Pharmacy, Key Laboratory of Bioactive Materials for the Ministry of Education, Nankai University, Tianjin 300350, China.
PMID: 41704759 DOI: 10.1016/j.isci.2026.114824
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.

Keywords
Biotechnology; Cancer; Molecular biology.
Products