Glucose addiction in cancer therapy : advances and drawbacks

Abstract

In contrast to differentiated normal cells, which primarily use mitochondrial respiration to generate the energy needed for cellular processes, most cancer cells rely on glycolysis, even in sufficient oxygen conditions, a phenomenon known as the “Warburg effect” or aerobic glycolysis. In the last years, much attention to the metabolic reprogramming of cancer cells has been paid by many research groups and, as a result, this altered energy metabolism was recognized in 2011 as one of the “hallmarks of cancer”. Aerobic glycolysis allows a 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. However, the search for suitable targets may be limited by the high plasticity of the metabolic network that can induce compensatory routes. Moreover, deregulated glucose metabolism has been also shown as a prominent feature associated with resistance to either 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 the different therapeutic strategies targeting the glucose “addiction” of tumor cells, highlighting the potential of these findings to be translated into effective weapons against cancer. Further, we will also present and discuss recent evidence for the involvement of glucose metabolism as a compensatory response to the use of drugs that target different signaling pathways, in which combination with glycolysis inhibitors are potentially useful.