Figure 6.

Therapeutic targeting of NADPH producing pathways in mitochondria impairs antioxidant defenses, leading to selective elimination of cancer cells. Inhibition of nicotinamide nucleotide transhydrogenase (NNT) (by a yet unidentified drug), of mitochondrial NAD kinase (NADK2) by thionicotinamide adenine dinucleotide (NADS) or by thionicotinamide adenine dinucleotide phosphate (NADPS), of ME2/3 by embonic acid (EA), of serine hydroxymethyltransferase 2 (SHMT2) by antifolate drugs, or of glutamate dehydrogenase 1 (GDH1) by R162 impairs NADPH production both in normal cells and in cancer cells. Elevation of reactive oxygen species (ROS) levels in cancer cells above the toxic threshold induces mitochondrial depolarization and release of cytochrome c in the intermembrane space (IMS). Treatment of cells with BH3 mimetics (such as ABT-199 or ABT-263), which cause opening of the BAX/BAK gateway, leads to massive release of cytochrome c in the cytosol and selective cell death of cancer cells. Inhibited proteins are white-colored.