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

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

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.

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