The majority of cancers of various tissue origin display wide portions suffering from insufficient respiration, due to permanent or transient hypoxia, which occurs during tumor development. This condition leads to the development of a glycolytic phenotype, where a compensatory lactate production takes place, in order to provide the cancer cells with sufficient amounts of energy and anabolites. Lactate is not just as a waste product of the glycolytic process, instead it plays a key role in the progression of cancer, since it promotes angiogenesis, cell migration, immune escape and radioresistance. Moreover, lactate can still constitute a metabolic fuel for oxidative tumor cells or vascular endothelial cells, and it can establish a symbiotic cell-cell shuttling system with stromal cells. Therefore, these peculiar roles of lactate in invasive tumors constitutes a high-priority target for future anti-cancer therapeutics [1]. Therapeutic interventions aimed at reducing lactate production in cancer tissues may consist of: a) reduction of glucose uptake (calorie-restricted ketogenic diet, physical exercise, inhibitors of glucose transporters); b) inhibition of enzymes involved in key-steps of glycolysis (inhibitors of hexokinase, phosphofructokinase, lactate dehydrogenase); c) block of the cellular trafficking of lactate (inhibitors of monocarboxylate transporters); d) enhancement of the mitochondrial oxidative metabolism (hyperbaric oxygen therapy, removal of inhibition of the Krebs cycle, for example, by using inhibitors of pyruvate dehydrogenase kinase) [2]. We have developed compounds that exert an anti-proliferative action on cancer cells by specific interventions on cancer metabolism, such as, inhibition of lactate dehydrogenase (LDH) activity [3,4], or reduction of glucose uptake through specific transmembrane transporters (GLUT) [5]. Furthermore, some of the LDH-inhibitors demonstrated a remarkable synergism with gemcitabine against pancreatic cancer cells in hypoxia [6]. and an improved activation of the redox-sensitive anti-cancer prodrug EO9 by means of an induced increase of the NADH/NAD+ cell ratio [7]. It is important to note that the development of agents that target lactate production, trafficking, and metabolism (by these or other methods) hold promise for treating nearly all invasive cancers, provided they present an appropriate therapeutic window. References 1) J. R. Doherty, J. L. Cleveland. J. Clin. Invest. 2013, 123, 3685–3692. 2) C. Granchi, F. Minutolo. ChemMedChem 2012, 7, 1318-1350. 3) C. Granchi, S. Roy, C. Giacomelli, et al. J. Med. Chem. 2011, 54, 1599–1612. 4) E. C. Calvaresi, C. Granchi, T. Tuccinardi, et al. ChemBioChem 2013, 14, 2263–2267. 5) T. Tuccinardi, C. Granchi, J. Iegre, et al. Bioorg. Med. Chem. Lett. 2013, 23, 6923–6927. 6) M. Maftouh, A. Avan, R. Sciarrillo, et al. Br. J. Cancer 2014, 110, 172-182. 7) S. J. Allison, J. R. P. Knight, C. Granchi, et al. Oncogenesis 2014, 3, e102; DOI: 10.1038/oncsis.2014.16.
Therapeutic Opportunities Offered by the Excessive Lactate Production in Cancer
MINUTOLO, FILIPPO
2014-01-01
Abstract
The majority of cancers of various tissue origin display wide portions suffering from insufficient respiration, due to permanent or transient hypoxia, which occurs during tumor development. This condition leads to the development of a glycolytic phenotype, where a compensatory lactate production takes place, in order to provide the cancer cells with sufficient amounts of energy and anabolites. Lactate is not just as a waste product of the glycolytic process, instead it plays a key role in the progression of cancer, since it promotes angiogenesis, cell migration, immune escape and radioresistance. Moreover, lactate can still constitute a metabolic fuel for oxidative tumor cells or vascular endothelial cells, and it can establish a symbiotic cell-cell shuttling system with stromal cells. Therefore, these peculiar roles of lactate in invasive tumors constitutes a high-priority target for future anti-cancer therapeutics [1]. Therapeutic interventions aimed at reducing lactate production in cancer tissues may consist of: a) reduction of glucose uptake (calorie-restricted ketogenic diet, physical exercise, inhibitors of glucose transporters); b) inhibition of enzymes involved in key-steps of glycolysis (inhibitors of hexokinase, phosphofructokinase, lactate dehydrogenase); c) block of the cellular trafficking of lactate (inhibitors of monocarboxylate transporters); d) enhancement of the mitochondrial oxidative metabolism (hyperbaric oxygen therapy, removal of inhibition of the Krebs cycle, for example, by using inhibitors of pyruvate dehydrogenase kinase) [2]. We have developed compounds that exert an anti-proliferative action on cancer cells by specific interventions on cancer metabolism, such as, inhibition of lactate dehydrogenase (LDH) activity [3,4], or reduction of glucose uptake through specific transmembrane transporters (GLUT) [5]. Furthermore, some of the LDH-inhibitors demonstrated a remarkable synergism with gemcitabine against pancreatic cancer cells in hypoxia [6]. and an improved activation of the redox-sensitive anti-cancer prodrug EO9 by means of an induced increase of the NADH/NAD+ cell ratio [7]. It is important to note that the development of agents that target lactate production, trafficking, and metabolism (by these or other methods) hold promise for treating nearly all invasive cancers, provided they present an appropriate therapeutic window. References 1) J. R. Doherty, J. L. Cleveland. J. Clin. Invest. 2013, 123, 3685–3692. 2) C. Granchi, F. Minutolo. ChemMedChem 2012, 7, 1318-1350. 3) C. Granchi, S. Roy, C. Giacomelli, et al. J. Med. Chem. 2011, 54, 1599–1612. 4) E. C. Calvaresi, C. Granchi, T. Tuccinardi, et al. ChemBioChem 2013, 14, 2263–2267. 5) T. Tuccinardi, C. Granchi, J. Iegre, et al. Bioorg. Med. Chem. Lett. 2013, 23, 6923–6927. 6) M. Maftouh, A. Avan, R. Sciarrillo, et al. Br. J. Cancer 2014, 110, 172-182. 7) S. J. Allison, J. R. P. Knight, C. Granchi, et al. Oncogenesis 2014, 3, e102; DOI: 10.1038/oncsis.2014.16.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
