Deregulation of cellular bioenergetics is currently being considered as one of the most significant hallmarks of cancer. In fact invasive tumors are characterized by a metabolic shift from oxidative phosphorylation to glycolysis for ATP generation, associated to high glucose uptake and elevated lactate production (Warburg effect). Several glycolytic enzymes are now being considered as promising targets for anticancer therapeutics. Among them, isoform 5 of lactate dehydrogenase (hLDH5), which is exclusively composed of LDH-A subunits, was found to play a key role in the progression of cancer, and several research groups have very recently reported various inhibitors of this enzyme. We have developed a new class of hLDH5-inhibitors based on an original N-hydroxyindole-2-carboxylate scaffold. These compounds generally proved to be efficient inhibitors of hLDH5 with Ki values in the low micromolar range. They showed a competitive behavior against both the substrate (pyruvate) and the cofactor (NADH), with a high degree of selectivity over the heart isoform (hLDH1, composed of LDH-B subunits). Moreover, they induced a significant reduction of the lactate production in cancer cells and displayed good anti-proliferative activities in vitro, thus showing a considerable potential as innovative anticancer agents.
Lactate dehydrogenase inhibitors in the "antiglycolytic" approach against cancer
GRANCHI, CARLOTTA;TUCCINARDI, TIZIANO;DI BUSSOLO, VALERIA;MACCHIA, MARCO;MARTINELLI, ADRIANO;GIANNACCINI, GINO;MINUTOLO, FILIPPO
2012-01-01
Abstract
Deregulation of cellular bioenergetics is currently being considered as one of the most significant hallmarks of cancer. In fact invasive tumors are characterized by a metabolic shift from oxidative phosphorylation to glycolysis for ATP generation, associated to high glucose uptake and elevated lactate production (Warburg effect). Several glycolytic enzymes are now being considered as promising targets for anticancer therapeutics. Among them, isoform 5 of lactate dehydrogenase (hLDH5), which is exclusively composed of LDH-A subunits, was found to play a key role in the progression of cancer, and several research groups have very recently reported various inhibitors of this enzyme. We have developed a new class of hLDH5-inhibitors based on an original N-hydroxyindole-2-carboxylate scaffold. These compounds generally proved to be efficient inhibitors of hLDH5 with Ki values in the low micromolar range. They showed a competitive behavior against both the substrate (pyruvate) and the cofactor (NADH), with a high degree of selectivity over the heart isoform (hLDH1, composed of LDH-B subunits). Moreover, they induced a significant reduction of the lactate production in cancer cells and displayed good anti-proliferative activities in vitro, thus showing a considerable potential as innovative anticancer agents.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
