Small-Molecule Targeting of VDAC Disrupts Mitochondrial Bioenergetics and Suppresses Melanoma Cell Survival and...

Melanoma is a highly aggressive and metabolically adaptable cancer that often resists conventional therapies. Targeting core bioenergetic pathways may, therefore, represent an effective strategy to improve therapeutic responses, particularly in tumors dependent on mitochondrial function. SC18 is an imidazolidine-2,4-dione compound that binds the NADH-binding pocket of voltage-dependent anion channels (VDACs), inducing mitochondrial dysfunction. VDAC expression is increased in melanoma and strongly associated with advanced disease stage and poor prognosis. In this study, we evaluated the effects of SC18 in melanoma cell lines with distinct pigmentation states, including melanin-rich melanotic human MNT-1 and mouse B16-F1, as well as low/amelanotic human SKMel28 and mouse YUMM cells. VDAC1, VDAC2 and VDAC3 were highly expressed across these melanoma lines, all of which relied on both glycolysis and mitochondrial oxidative phosphorylation for ATP production. SC18 reduced mitochondrial membrane potential and oxygen consumption rates, accompanied by declines in intracellular ATP levels and TCA cycle substrate utilization. SC18 also increased reactive oxygen species, mitochondrial superoxide, and lipid peroxidation, indicating enhanced oxidative stress. These metabolic and redox disturbances were associated with reduced cell viability and significantly impaired migration in multiple melanoma cell lines, supporting a potential anti-metastatic effect. In addition, SC18 showed synergistic cytotoxicity when combined with other chemotherapeutic agents. Overall, SC18 disrupted mitochondrial metabolism, induced oxidative stress, and impaired survival and motility pathways, with more pronounced effects in low/amelanotic than in melanotic melanoma cells. Together, these findings support the further development of SC18 as a mitochondrial metabolic disruptor that targets redox vulnerabilities in melanoma.