Tackling tumors by exploiting their glucose avidity and high rate of glycolysis

Most cancers of various tissue origin show large portions suffering from permanent or transient hypoxia, which takes place during tumor development. This situation leads to an increase of the glycolytic metabolism leading to the production of lactate, which provides cancer cells with adequate amounts of energy. In order to do so, cancer cells often display an overexpression of glucose transporters (GLUTs), in particular of GLUT1, which results in an augmented glucose uptake. This is due to the fact that neoplastic cells need enhanced glucose supply to support their less efficient energy production by means of anaerobic glycolysis (Warburg effect). This peculiar metabolic switch can be effectively utilized for both diagnostic and therapeutic purposes. As a matter of fact, a widely diffused clinical application that exploits the increased uptake of glucose into cancerous over normal tissues consists in the administration of the radiolabeled glucose analogue 18F-FDG as an ubiquitous imaging tool for cancer diagnosis. Furthermore, therapeutic interventions aimed at reducing cancer glycolysis may be implemented by several strategies, such as, for example: 1) reduction of glucose uptake (calorie-restricted ketogenic diet, physical exercise, inhibitors of glucose transporters); 2) inhibition of enzymes involved in key-steps of glycolysis (hexokinase, phosphofructokinase, lactate dehydrogenase); 3) block of the cellular trafficking of lactate (monocarboxylate transporters); 4) enhancement of the mitochondrial oxidative metabolism (hyperbaric oxygen therapy, removal of inhibition of the Krebs cycle). We have developed various classes of compounds that produce an anti-proliferative effect in cancer cells by specific interventions on cancer metabolism. For examples, some compounds proved to be able to inhibit lactate dehydrogenase (LDH) activity, or to reduce glucose uptake through GLUTs. Furthermore, some of these compounds demonstrated a remarkable synergism with other antineoplastic agents with different mechanisms of action.