Second, nonessential AAs can be synthesized by tumor and normal cells from precursors circulating in the blood, thus making general protein restriction unnecessary. metabolic heterogeneity. These techniques could also be useful to follow dynamical evolution of tumor metabolism during disease progression or in response to therapies (8, 9). In the first part of this review we analyze H-1152 the main metabolic cascades that are deregulated in tumors. A clear understanding of these pathways and their role in tumor cell proliferation and survival is essential to identify targets for effective therapies. In the second and third parts of the manuscript, we respectively review the dietary and pharmacological strategies that hold promise to successfully target tumor metabolism on the basis of available preclinical evidence. Metabolic pathways that sustain cancer cell survival and proliferation Glucose Upregulated aerobic glycolysis provides several benefits to cancer cells (5). First, at physiological blood concentrations, glucose ensures sufficiently fast ATP production to fulfill energetic demands, while contemporarily fueling anabolic processes through biomass production; second, pyruvate-derived lactate, when excreted, creates an extracellular acid environment that recruits macrophages and other immune cells, thus favoring metastatization; third, pyruvate can be used to produce oxaloacetate (OAA) and the amino acids (AAs) alanine and aspartate, which take part in the synthesis of proteins or other biomolecules (5, 10). In summary, aerobic glycolysis can fulfill most of the energetic and metabolic needs of highly proliferating cancer cells, including AA biosynthesis when a proper source of nitrogen groups (usually deriving from glutamine) is also provided. In tumors, aerobic glycolysis is often stimulated by oncogenes, including PI3K and RAS, which induce expression of the glucose transporter gene and of the glycolytic enzymes hexokinase (HK) and phosphofructokinase (PFK), and contemporarily inhibit mitochondrial oxidation of pyruvate (Figure 1). Recent studies on tumors showed that part of glucose-derived pyruvate can be diverted into the mitochondrial tricarboxylic acid (TCA) cycle to produce additional energy or intermediates for synthesis of fatty acids (FAs) or other nonessential AAs, such as glutamate and glutamine H-1152 (11, 12). While reducing the dominance of aerobic glycolysis as the primary source of energy and anabolic precursors for rapidly proliferating tumor cells, these studies confirm glucose as the major metabolic substrate for malignancies. Preclinical evidence suggests that targeting deregulated glucose metabolism is a potentially effective anticancer approach. Indeed, reducing extracellular glucose or inhibiting glycolysis through 2-deoxy-D-glucose (2-DG) induces proliferation arrest in several cancer cell lines and also synergizes with cytotoxic treatments to activate apoptosis (13, 14); these effects are especially strong in cells with compromised mitochondrial oxidative phosphorylation (15). Inhibiting lactate production by the lactate dehydrogenase A (LDHA) enzyme is another way to halt glycolysis progression by preventing NAD+ regeneration from NADH, which is toxic to highly glycolytic cancer cells (16). Moreover, dietary regimens that reduce glycemia also enhance the antitumor activity of chemotherapy and prolong survival of mice xenografted with human tumor cells (13). Finally, the hyperglycemic/diabetic state is associated with worse prognosis in glioblastoma multiforme (GBM), colorectal cancer and acute leukemia patients (17C20). Two different approaches can be exploited to target aerobic glycolysis in cancer therapy: reducing blood glycemia (systemic approach), or inhibiting specific enzymes in the glycolytic cascade (cell-autonomous approach). The former strategy requires a careful selection of patient subgroups that, based on their glycemic state (hyperglycemic versus euglycemic), tumor avidity for glucose as detected through 18FDG-PET, or molecular tumor profile (e.g. RAS or PI3K activation), are more likely to benefit from it. In the cell-autonomous approach, H-1152 the most suitable molecular targets need to be identified, and potent and selective inhibitors to be synthesized. Amino acids (AAs) Unrestrained tumor proliferation requires continuous replenishment of AAs to be used as building blocks for structural and enzymatic proteins, as precursors of essential biochemical components, including FAs, other AAs, nucleotides and the antioxidant glutathione, or, finally, as monocarbon unit donors. Similar to normal.The role of low-dose aspirin in established cancers is more uncertain, and ongoing prospective studies are investigating it as an adjuvant treatment after radical surgery. Targeting aerobic glycolysis The most direct way to target exaggerated aerobic glycolysis in tumors is to reduce glucose availability to cancer cells, which can be achieved through either dietary or pharmacological (e.g. during disease progression or in response to therapies (8, 9). In the first part of this review we analyze the main metabolic cascades that are deregulated in tumors. A clear understanding of these pathways and their role in tumor cell proliferation and survival is essential to identify targets for effective therapies. In the second and third parts of the manuscript, we respectively review the dietary and pharmacological strategies that hold promise to successfully target tumor metabolism on the basis of available preclinical evidence. Metabolic pathways that sustain cancer cell survival and proliferation Glucose Upregulated aerobic glycolysis provides several benefits to cancer cells (5). First, at physiological blood concentrations, glucose ensures sufficiently fast ATP production to fulfill energetic demands, while contemporarily fueling anabolic processes through biomass production; second, pyruvate-derived lactate, when excreted, creates an extracellular acid environment that recruits macrophages and other immune cells, thus favoring metastatization; third, pyruvate can be used to produce oxaloacetate (OAA) and the amino acids (AAs) alanine and aspartate, which take part in the synthesis of proteins or other biomolecules (5, 10). In summary, aerobic glycolysis can fulfill most of the energetic and metabolic needs of highly proliferating cancer cells, including AA biosynthesis when a proper source of nitrogen groups (usually deriving from glutamine) is also provided. In tumors, aerobic glycolysis is often stimulated by oncogenes, including PI3K and RAS, which induce expression of the glucose transporter gene and of the glycolytic enzymes hexokinase (HK) and phosphofructokinase (PFK), and contemporarily inhibit mitochondrial oxidation of pyruvate (Figure 1). Recent studies on tumors showed that part of glucose-derived pyruvate can be diverted into the mitochondrial tricarboxylic acid (TCA) cycle to produce additional energy or intermediates for synthesis of fatty acids (FAs) or other nonessential AAs, such as glutamate and glutamine (11, 12). While reducing the dominance of aerobic glycolysis as the primary H-1152 source of energy and anabolic precursors for rapidly proliferating tumor cells, these studies confirm glucose as the major metabolic substrate for malignancies. Preclinical evidence suggests that targeting deregulated glucose metabolism is a potentially effective anticancer approach. Indeed, reducing extracellular glucose or inhibiting glycolysis through 2-deoxy-D-glucose (2-DG) induces proliferation arrest in H-1152 several cancer cell lines and also synergizes with cytotoxic treatments to activate apoptosis (13, 14); these effects are especially strong in cells with compromised mitochondrial oxidative phosphorylation (15). Inhibiting lactate production by the lactate dehydrogenase A (LDHA) enzyme is another way to halt glycolysis progression by preventing NAD+ regeneration from NADH, which is toxic to highly glycolytic cancer cells (16). Moreover, dietary regimens that reduce glycemia also enhance the antitumor activity of chemotherapy and prolong survival of mice xenografted with human tumor cells (13). Finally, the hyperglycemic/diabetic state is associated with worse prognosis in glioblastoma multiforme (GBM), colorectal cancer and acute leukemia patients (17C20). Two different approaches can be exploited to target aerobic glycolysis in cancer therapy: reducing blood glycemia (systemic Mouse monoclonal to HK2 approach), or inhibiting specific enzymes in the glycolytic cascade (cell-autonomous approach). The former strategy requires a careful selection of patient subgroups that, based on their glycemic state (hyperglycemic versus euglycemic), tumor avidity for glucose as discovered through 18FDG-PET, or molecular tumor profile (e.g. RAS or PI3K activation), will reap the benefits of it. In the cell-autonomous strategy, the best option molecular targets have to be discovered, and potent and selective inhibitors to become synthesized. Proteins (AAs) Unrestrained tumor proliferation needs constant replenishment of AAs to be utilized as blocks for structural and enzymatic proteins, as precursors of important biochemical elements, including FAs, various other AAs, nucleotides as well as the antioxidant glutathione, or, finally, as monocarbon.
Second, nonessential AAs can be synthesized by tumor and normal cells from precursors circulating in the blood, thus making general protein restriction unnecessary
