Inhibitory activity of human lactate dehydrogenase isoform A and B (LDH-A, LDH-B) by new potential anticancer drugs

The glycolysis is the stage of the production of energy by breakdown of glucose in body cells; a chain of chemical events requiring a specific set of enzymes, and resulting in formation of ATP. In aerobic metabolism subsequent sequences produce several times more ATP, thereby providing a greater quantity of energy per molecule of glucose, utilizing oxygen, and producing carbon dioxide and water-comparable to burning organic fuels in air. In anaerobic metabolism glycolysis is the only means of energy production from glucose and lactate is the end-product. This occurs in cells which cannot utilize oxygen, predominately in some components of skeletal muscle, and probably to some extent in all cells when there is a shortage of oxygen Many substances have been developed which inhibit glycolysis, and such glycolytic inhibitors are currently the subject of intense research as anticancer agents. Some glycolytic inhibitors currently being studied as anticancer treatments. Highly invasive tumor cells are characterized by a metabolic switch, known as the Warburg effect. The Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria like most normal cells. The latter process is aerobic. Malignant rapidly-growing tumor cells typically have glycolytic rates that are up to 200 times higher than those of their normal tissues of origin; this occurs even if oxygen is plentiful. This dependence on glycolysis also confers a growth advantage to cells present in hypoxic regions of the tumor. One of the key enzymes involved in glycolysis, the muscle isoform of lactate dehydrogenase (LDH-A), is overexpressed by metastatic cancer cells and is linked to the vitality of tumors in hypoxia. Lactate dehydrogenase (LDH) is a widely diffused 2-hydroxyacid oxidoreductase, which promotes the inter-transformation of pyruvate and lactate by using a nicotinamide adenine dinucleotide cofactor (NADH/NAD+). Various isoforms of LDH are presently being considered as promising targets for a range of pathologies, such as cancer and malaria. This enzyme may be considered as a potential target for new anticancer agents, since its inhibition cuts cancer energetic and anabolic supply, thus reducing the metastatic and invasive potential of cancer cells. With colorimetric measurement of inhibition (% relative to control) of the enzymatic activity of LDH-A and LDH-B in the presence of compounds, we have discovered new and efficient N-hydroxyindole-based and Triazole-substituted N-hydroxyindol-2-carboxylates inhibitors of LDH-A, which are isoform-selective (over LDH-B) and competitive with both the substrate (pyruvate) and the cofactor (NADH)