Ascorbate Enhances the Cytotoxicity of the Manganese–Curcumin–Triphenylphosphonium Complex in Human Cancer Cells

Background/Objectives: Manganese–Curcumin–Triphenylphosphonium (Mn-C-TPP), a complex designed for mitochondrial targeting, was investigated with ascorbate to assess cytotoxicity and associated cellular responses. We hypothesized that Mn-C-TPP would amplify ascorbate-driven oxidative stress and produce synergistic cytotoxicity in susceptible cancer cell lines. Methods: An inverse, control-normalized SYTOX-derived response index (vehicle = 100; staurosporine = 0) was determined after 72 h in HCT116, A549, HepG2, and normal dermal human fibroblasts (NDHFs). H2O2-associated luminescence (ROS-Glo), caspase-3/7 activation, and mitochondrial membrane potential were assessed in selected cancer cell lines. Drug interactions were analyzed using SynergyFinder 3.0 (ZIP model). Results: Mn-C-TPP alone reduced the SYTOX-derived response index in HCT116 and HepG2, whereas A549 and NDHF showed smaller changes. Ascorbate enhanced cytotoxicity at selected combinations. In HCT116, 3 µM Mn-C-TPP plus 100 µM ascorbate decreased the SYTOX-derived response index toward the staurosporine reference. HepG2 responded markedly to 3–7 µM Mn-C-TPP with 100–300 µM ascorbate, whereas pronounced A549 responses occurred mainly at 15–30 µM Mn-C-TPP with 100–300 µM ascorbate. Mean ZIP scores were approximately 32, 54, 6, and 10 for HCT116, HepG2, A549, and NDHF, respectively. The NDHF response index remained close to the vehicle reference at lower combination doses but decreased at higher doses. Cellular assays showed increased H2O2-associated luminescence with Mn-C-TPP alone and higher mean signals with selected combinations than with ascorbate alone, together with caspase-3/7 activation and mitochondrial depolarization. Conclusions: These findings demonstrate cell-line- and concentration-dependent cytotoxicity and support further investigation of the proposed mitochondrial redox mechanism.