Halogen substituted 4-thio-2′-deoxyuridines as photosensitizers for the photodynamic therapy of prostate cancer. An in vitro study

Photodynamic therapy (PDT) is a minimally invasive modality that employs a photosensitizer (PS) and light exposure source within the PS's optimal absorption range to induce selective cytotoxic effects. This study investigates 5'-bromo-4-thio-2'-deoxyuridine (BrSdU) and 5'-iodo-4-thio-2'-deoxyuridine (ISdU), both modified nucleoside (MN)-based photosensitizers. The presence of the sulfur atom in their thionucleoside structures shifts their maximum absorption to approximately 350 nm, enabling efficient activation under UVA irradiation and minimizing the inner filter effect observed with conventional halogenated nucleosides. MTT assays confirm that BrSdU and ISdU exhibit negligible dark cytotoxicity in PC3 prostate cancer cells. In contrast, clonogenic assays reveal that UVA irradiation of BrSdU/ISdU-labeled cells significantly enhances cell lethality. Mechanistic analysis demonstrates that the combined treatment induces (1) a decrease in viable cell population with a concomitant increase in early apoptotic cells, (2) G2/M phase cell cycle arrest, (3) elevated levels of DNA double-strand breaks compared to UVA-only controls, and (4) no significant alteration in intracellular reactive oxygen species (ROS) levels. These results suggest that BrSdU and ISdU function as effective UVA-activated photosensitizers, mediating DNA-targeted photodynamic damage through mechanisms largely independent of ROS generation, and hold promise for further development in targeted cancer therapies.