A novel stilbene derivative targets RAD51 activity and sensitizes DU145 prostate cancer cells to cisplatin

Homologous recombination (HR) is a high-fidelity DNA repair pathway responsible for the resolution of double-strand breaks, with the RAD51 recombinase playing a pivotal role through the formation of nucleoprotein filaments on single-stranded DNA. Overexpression of RAD51 is frequently observed in cancer cells, where it promotes genome stability under genotoxic stress and contributes to acquired resistance to DNA-damaging chemotherapeutic agents. In this study, we report the identification of a novel stilbene-derived compound, the disodium salt of 4,4'-diphenylcarbamate stilbene-2,2'-disulfonic acid (DPDS), as a novel compound that modulates RAD51 monomer-monomer interactions and reduces its binding to single-stranded DNA and ATP, processes that are critical for filament assembly and homologous recombination. Furthermore, DPDS enhances the cytotoxic effect of cisplatin in DU145 prostate cancer cells and was associated with reduced RAD51 nuclear foci formation and increased accumulation of DNA double-strand breaks. Notably, DPDS did not significantly affect cell viability in the four cellular models evaluated under our experimental conditions and displayed lower intrinsic cytotoxicity than DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid) and emzadirib. Collectively, these findings support that DPDS as a chemical modulator of RAD51 activity may enhance cisplatin sensitivity in DU145 prostate cancer cells.