Inhibiting Lactate Dehydrogenase A Enhances the Cytotoxicity of the Mitochondria Accumulating Antioxidant, Mitoquinone, in Melanoma Cells
Alshamrani, Ali A. . 2016
Limited options exist for inhibitors targeted against melanoma tumors with mutation subtypes other than BRAF. We investigated the cytotoxic activity of mitoquinone (MitoQ), an antioxidant and ubiquinone derivative, on various human melanoma cell lines, alone or in combination with other agents to perturb cellular bioenergetics. This lipophilic cation crosses the cell membrane, enters and accumulates in the mitochondria where it can disrupt mitochondrial function at micromolar concentrations or act as an antioxidant to preserve membrane integrity at nanomolar concentrations. Consistent with previous studies, cells treated with 12.5 μM MitoQ show significantly reduced viability versus control treatments. Although all melanoma cells were susceptible to cytotoxicity induced by MitoQ, cells with wild-type BRAF were responsive to lower doses, compared to cells with activating mutations in BRAF. Mechanistically, the positively charged lipophilic moiety of the MitoQ induced a dose-dependent collapse of the mitochondrial membrane potential (Δψm) and significantly reduced the mitochondrial ATP production and reduced oxygen consumption rate, suggesting mitochondrial dysfunction. We also combined MitoQ with a glycolytic lactate dehydrogenase A inhibitor (FX-11) and observed an enhanced reduction in viability, but not other therapies examined. To summarize, the data suggest that FX-11 enhances the cytotoxic effects of MitoQ in cells with wild-type BRAF.
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