Prodrug-like Quinone Containing Two Redox-Active Centers Induces Ferroptosis in Prostate Cancer Cells with Cytotoxic Action Partially Depending on NAD(P)H Quinone Dehydrogenase 1 (NQO1)

Abstract

Naphthoquinones are redox-active compounds with antitumor potential, often linked to NQO1 overexpression in cancer cells. This study evaluated the cytotoxic activity of two synthetic 1,4-naphthoquinones, compound 1 and its dual redox analog, compound 4, against NQO1-overexpressing DU-145 prostate cancer cells through integrated in vitro, enzymatic, and computational (docking and quantum) analyses. Compound 4 exhibited over 2-fold greater cytotoxicity against DU-145 cells compared to nontumor MRC-5 cells, while maintaining low hemolytic activity. Evidence of membrane damage, ROS generation, lipid peroxidation, and reversal by deferoxamine indicated ferroptosis induction by 4, whereas 1 triggered caspase-3-dependent apoptosis. Both caused ROS-mediated DNA damage attenuated by NAC. Docking and enzymatic assays confirmed partial dependence on NQO1, with 4 showing greater ROS production despite lower enzymatic activity. Overall, compound 4 highlights the potential of dual-redox quinone platforms to induce ferroptosis, providing a viable lead candidate for novel antineoplastic drug discovery in prostate cancer and other malignancies.