Targeting Energy Metabolism in Cancer Treatment

Abstract

Cancer is the second most common cause of death worldwide after cardiovascular diseases. The development of molecular and biochemical techniques has expanded the knowledge of changes occurring in specific metabolic pathways of cancer cells. Increased aerobic glycolysis, the promotion of anaplerotic responses, and especially the dependence of cells on glutamine and fatty acid metabolism have become subjects of study. Despite many cancer treatment strategies, many patients with neoplastic diseases cannot be completely cured due to the development of resistance in cancer cells to currently used therapeutic approaches. It is now becoming a priority to develop new treatment strategies that are highly effective and have few side effects. In this review, we present the current knowledge of the enzymes involved in the different steps of glycolysis, the Krebs cycle, and the pentose phosphate pathway, and possible targeted therapies. The review also focuses on presenting the differences between cancer cells and normal cells in terms of metabolic phenotype. Knowledge of cancer cell metabolism is constantly evolving, and further research is needed to develop new strategies for anti-cancer therapies.

Keywords: cancer metabolism; cancer treatment; glycolysis; oxidative phosphorylation.

Figure 1

Graphical representation of inhibitors of glucose transport, glycolysis pathway, 6GPDH, and its metabolic target. GLUT—glucose transporter; HK2—hexokinase type 2; 2-DG—2-deoxyglucose; 3-BP—3-bromopyruvate; BNBZ—benitrobenrazide; DHEA—dehydroepiandosterone; 6-AN—6-aminonicotinamide; ZA—zoledronic acid; 6GPDH—glucose-6-phosphate dehydrogenase; PGI—phosphoglucose isomerase; PFK1—phosphofructokinase 1; ALDO—aldolase; TIM—triosephosphate isomerase; GAPDH—glyceraldehyde 3-phosphate dehydrogenase; KA—koningic acid; MG—methylglyoxal; PGK1—phosphoglycerate kinase 1; PGAM1—phosphoglycerate mutase 1; EGCG—epigallocatechin-3-gallate; ENO2—γ-enolase; PK—pyruvate kinase; LDH—lactate dehydrogenase; MCT1—monocarboxylate transporter 1.

Figure 2

Schematic representation of glutamine transport, glutaminolysis pathway inhibitors, and its metabolic target. SLC1A5—glutamine transporter; GPNA—L-γ-glutamyl-p-nitroanilide; DON—6-diazo-5-oxo-L-norleucine; EGCG—epigallocatechin-3-gallate; GLS—glutaminase; GDH—glutamate dehydrogenase.

Figure 3

Graphical representation of pyruvate dehydrogenase complex (PDH), aconitase (ACO), isocitrate dehydrogenase 2 (IDH2), fatty acid synthesis, as well as metabolism inhibitors and their metabolic target. DCA—dichloroacetate; ACO—aconitase; ACLY—citrate lyase ATP; ACC—acetyl-CoA carboxylase; FASN—fatty acid synthase; ACS—acetyl-CoA synthetase; CPT1—carnitine palmitoyltransferase 1; CPT2—carnitine acyltransferase 2; CACT—carnitine-acylcarnitine translocase.