A combination of 2-deoxy-d-glucose and 6-aminonicotinamide induces oxidative stress mediated selective radiosensitization of malignant cells via mitochondrial dysfunction

Oxidative stress-mediated mitochondrial dysfunction is known to induce intrinsic pathway of apoptosis. Previously, we have shown that a combination of metabolic modifiers 2-deoxy-D-glucose (2-DG) and 6-aminonicotinamide (6-AN) results in oxidative stress-mediated radiosensitization of malignant cells via noncoordinated expression of antioxidant defense. We now show that the combination (2-DG + 6-AN + 2Gy) induces significant alterations in mitochondrial membrane potential and oxidative damage to lipid and proteins selectively in malignant cells resulting in the release of cytochrome c from mitochondria and increase in Bax/Bcl-2 ratio stimulating intrinsic pathway of apoptosis, besides enhancing the mitotic death linked to cytogenetic damage. These results highlight the role of mitochondrial dysfunction in selective radiosensitization by 2-DG + 6-AN, besides inhibition of energy-linked DNA repair processes and generation of oxidative stress reported earlier.