Exploring Potential for Repurposing Antiretroviral Drugs Etravirine and Efavirenz in Prostate and Bladder Cancer

<b>Background/Objectives:</b> Prostate and bladder cancers are significant global health challenges with increasing incidence and limited treatment options in advanced stages. Drug repurposing offers a cost-effective strategy to accelerate the development of new anticancer therapies. This study investigated the antitumor activity of the non-nucleoside reverse transcriptase inhibitors efavirenz (EFV) and etravirine (ETV) in prostate and bladder cancer models. <b>Methods:</b> PC-3 prostate cancer and UM-UC-5 bladder cancer cell lines were treated with EFV, ETV, or their combination. Cell viability was assessed at 24, 48, and 72 h to evaluate time and concentration-dependent effects. Wound-healing assays were used to measure cell migration, and clonogenic assays assessed long-term proliferative capacity. <b>Results:</b> Both EFV and ETV decreased cell viability in a time and dose-dependent manner. ETV showed greater potency in PC-3 cells, while EFV demonstrated more consistent effects in UM-UC-5 cells. Combination treatment enhanced cytotoxicity, particularly at 48 and 72 h, suggesting potential synergy. Wound-healing assays indicated impaired migration in UM-UC-5 cells treated with ETV or the EFV + ETV combination. Clonogenic assays confirmed reduced long-term proliferation in both cell lines following treatment. <b>Conclusions</b>: EFV and ETV exhibit selective anticancer activity in prostate and bladder cancer cells, with enhanced effects when combined. These findings support their potential as repurposed therapeutic agents and warrant further preclinical evaluation for prostate and bladder cancer therapy.