Innovative Se-Flutamide Derivatives: Enhanced Activity Toward Androgen Receptor (AR)-Dependent and -Independent Prostate Cancer Cells

Sixteen novel selenoderivatives of flutamide, which is used for treating androgen receptor (AR)-dependent prostate cancer, were developed. All the Se derivatives displayed promising activity against the NCI-60 human cancer cell line panel, which also includes two AR-independent prostate cancer cell lines, DU-145 and PC-3. Conversely to flutamide, compounds a2, a5, and b4 exhibited a potent antiproliferative effect toward AR-dependent LNCaP cells. Several cell death inhibitors were used to determine the underlying regulated cell death processes of a5. Regarding its mechanism of action in these cells, this compound promoted apoptosis by activating both intrinsic and extrinsic apoptotic pathways, without generating reactive oxygen species (ROS). Besides, it induced the G0/G1 cell cycle arrest. Altogether, it could be concluded that this Se-flutamide analog could be a feasible and promising candidate for further development for the treatment of both AR-dependent and -independent prostate cancers.