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.