Figure 1
From: Energy disruptors: rising stars in anticancer therapy?
Molecular and cellular mode of action of energy disruptors. 2-Deoxyglucose inhibits glycolysis, it is phosphorylated by the hexokinase (HK) to produce 2-deoxglucose-6-phosphate (2-DG-6-P). Biguanides (metformin and phenformin) inhibit complex 1 of the electron transport chain (complexes 1 to 4 and the F0F1 ATP synthase). AICAR is converted in ZMP which activates the AMP-activated kinase (AMPK). The glycolysis converts glucose in pyruvate via a sequence of enzymatic reactions. The lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate into lactate. Pyruvate can be addressed to the mitochondria and converted into acetyl-CoA by the pyruvate dehydrogenase (PDH), acetyl-CoA is then processed by the tricarboxylic acid (TCA) cycle. The TCA produces important intermediates but also cofactors (NADH and FADH2) required by the electron transport chain. The AMPK is phosphorylated by LKB1 or the CAMKK2 and activates TSC2 an inhibitor of mTORC1. It also inhibits and phosphorylates the acetyl-CoA carboxylase (ACC), the enzyme that converts the acetyl-CoA into malonyl-CoA, an inhibitor the Carnitine palmitoyltransferase-1 (CPT-1). Akt is activated by growth factors and PTEN is a negative regulator of the PI3K/Akt pathway. Akt phosphorylates and inhibits TSC2. CAMKK2, calcium/calmodulin-dependent protein kinase kinase 2; GSH, glutathione; PFK-1, phosphofructokinase-1; PHGDH, phosphoglycerate dehydrogenase; PI3K, phosphoinositide 3-kinase; TRX, thioredoxin; TSC2, tuberous sclerosis 2.
