Targeting Cancer with Redox Catalysis: Manganese Porphyrins and Ascorbate Synergistically Induce Selective Oxidative Stress and Necrotic Cell Death

Background: The combination of manganese porphyrins (MnPs) and ascorbate (ASC) represents a promising redox-based therapeutic approach for selectively targeting cancer cells. In this study, we investigated the cytotoxic effects of two structurally distinct MnPs (MnTPPS and MnF₂BMet) with differing lipophilicity and potential membrane permeability in combination with ASC. Methods: Human cancer cell lines (MCF-7, PANC-1, U87, T98G, AT-2), and normal human dermal fibroblasts (HDF), were treated with MnTPPS and MnF₂BMet in the absence or presence of ASC. Their viability and invasive potential were then assessed with single-cell methods along with the analyses of intracellular oxidative stress. Results: MnPs alone exhibited no intrinsic cytostatic or cytotoxic activity, as confirmed by proliferation, viability, and motility assays. When combined with ASC, both MnTPPS and MnF₂BMet significantly enhanced ASC-induced oxidative stress, leading to lipid peroxidation, glutathione depletion, mitochondrial dysfunction, and cell membrane disruption. Time-lapse microscopy revealed rapid necrotic cell death under co-treatment. The cytotoxic effect was completely abolished by catalase, indicating the essential role of hydrogen peroxide. In contrast, dehydroascorbate (DHA), which increases intracellular ASC levels, did not reproduce the same toxicity, suggesting that extracellular ROS gener ation contributes predominantly to the observed effects. Normal fibroblasts were minimally affected, supporting the selectivity of the MnPs–ASC system toward cancer cells. Conclusions: The results indicate that MnTPPS and MnF₂BMet enhance extracellular oxidation of ascorbate and subsequent ROS production, leading to selective oxidative stressmediated cancer cell death. This study supports the potential of MnPs–ASC redox catalysis as a complementary oxidative stress–based anticancer strategy and highlights the need for further mechanistic and structure–activity investigations.