Repurposing Antiretroviral Drugs for Urological Cancers: Differential Effects of Protease Inhibitors and NNRTIs on Prostate and Bladder Cancer Cells

Drug repurposing presents as a promising strategy in oncology, particularly for urological prostate and bladder cancers, where resistance to current therapy remains a challenge. This study evaluated the anticancer potential of three antiretroviral drugs, namely ritonavir (RIT), saquinavir (SAQ), and rilpivirine (RPV), in PC-3 and UM-UC-5 cancer cell lines, using MTT, clonogenic, wound healing, toxicity assessment with fibroblast cells, and DCFDA assays; this last method included efavirenz (EFV) and etravirine (ETV) for intracellular reactive oxygen species (ROS) production. RIT and SAQ showed stronger antiproliferative effects than RPV, with lower concentration- and cell-line-dependent activity, while clonogenic assays confirmed a reduction in long-term proliferation, particularly for RIT in both cell lines and SAQ for UM-UC-5. In contrast, effects on cell migration were limited for all drugs. ROS production was cell-dependent, with EFV increasing ROS in PC-3 and SAQ and RIT in UM-UC-5 cells. Generally, all drugs showed minimal toxicity in non-malignant cells, with SAQ exhibiting some toxicity but only for concentrations higher than those required for anticancer activity. Overall, these findings suggest that antiretroviral, especially protease inhibitors, may cause anticancer effects, although these are concentration- and context-dependent, and further investigation is needed to understand the mechanisms involved.