8-(4-Trifluoromethylthio)benzylamino-2'-deoxyadenosine: a purine nucleoside as a potential radiosensitizer

DNA damage induced by hydroxyl radicals may be insufficient to achieve optimal radiotherapy outcomes in solid tumors. To counteract this limitation, radiosensitizers are used in conjunction with ionizing radiation. In this study, we identify 8-(4-Trifluoromethylthio)benzylamino-2'-deoxyadenosine (dA-NHbenzylSCF₃) as a potential radiosensitizer through computational modeling. Its efficacy is further substantiated by stationary radiolysis experiments and in vitro studies using prostate (PC3) and breast cancer (MCF-7) cell lines. Importantly, the compound exhibits no cytotoxic effects on these cancer cells or human mammary fibroblasts (HMF). Clonogenic assay demonstrates a significant reduction in cell survival following irradiation. Flow cytometry analyses indicate that dA-NHbenzylSCF₃ enhances DNA double-strand break formation (DSBs) and induces apoptosis without perturbing cell cycle progression. Cellular uptake studies reveal its predominant cytoplasmic localization, with partial nuclear distribution. Furthermore, the compound is neither phosphorylated by cellular kinases nor incorporated into genomic DNA. These findings underscore dA-NHbenzylSCF₃ as a promising radiosensitizer for improving radiotherapy outcomes.