Glucose addiction in cancer therapy: advances and drawbacks

Abstract

While normal differentiated cells primarily use mitochondrial respiration to generate the required energy for cellular processes, most cancer cells rely on glycolysis, even in sufficient oxygen conditions. This phenomenon is known as the "Warburg effect" or aerobic glycolysis and the metabolic reprogramming of cancer cells towards this altered energy metabolism is currently recognized as one of the "hallmarks of cancer". Aerobic glycolysis underlies the rapid growth of tumor cells, with high rates of glucose consumption and lactic acid production, leading to cellular acidosis. Metabolic reprogramming renders cancer cells dependent on specific metabolic enzymes or pathways that could be exploited in cancer therapy. The development of treatments that target tumor glucose metabolism is receiving renewed attention, with several drugs targeting metabolic pathways currently in clinical trials. The search for suitable targets, however, is limited by the high plasticity of the metabolic network that can induce compensatory routes. Deregulated glucose metabolism is a prominent feature associated with resistance to classical chemotherapy or oncogene-targeted therapies, strengthening the clinical potential of combining these therapies with glycolysis inhibitors. The aim of this review is to compare the advances of different therapeutic strategies targeting the glucose "addiction" of tumor cells, highlighting their potential as effective weapons against cancer. We further discuss recent evidence for the involvement of glucose metabolism as a compensatory response to the use of drugs that target different signaling pathways, where the combination with glycolysis inhibitors could prove extraordinarily useful.

Pheochromocytoma: The First Metabolic Endocrine Cancer

“…Glucose metabolism can be therapeutically altered at two levels: 1) glucose uptake (inhibition of glucose transporters) and 2) glycolytic enzymes (e.g. hexokinase 2, LDH, or PDK inhibitors) (85, 86). Another option is inhibitors of glutaminolysis or SLC1A5 glutamine transporter (87).…”

The metabolic microenvironment of melanomas: Prognostic value of MCT1 and MCT4

“…1 Importantly, this metabolic reprogramming was recently identified as one of the hallmarks of cancer 2 and has been pointed out as a promising target for anti-cancer therapy. 3 Aerobic glycolysis results in a high production of free protons and lactate that must be shuttled to the extracellular milieu through many transporters. 4 The resultant microenvironment selects for cells with enhanced metastatic potential and is associated with evasion to immune destruction and resistance to radio-and chemotherapy.…”

Impact of Metabolism in on T-Cell Differentiation and Function and Cross Talk with Tumor Microenvironment

“…Increased glucose uptake lead to upregulated glycolysis and thus more pyruvate is produced even in normoxia conditions. Under limited oxygen availability (hypoxia), more pyruvate avoids TCA cycle and generates excess of lactate secreted thereby in the tumor microenvironment (118, 119). In addition to its central role as a carbohydrate nutrient for ATP synthesis, new evidence revealed that high glucose uptake is also important for biomass synthesis needed for rapidly proliferating cancer cells.…”