Anticancer Agents That Counteract Tumor Glycolysis

Abstract

Can we consider cancer as a “metabolic disease”? Tumors are the result of a metabolic selection, forming tissues composed of heterogeneous cells that generally express an overactive metabolism as a common feature. In fact, cancer cells have to deal with increased needs for both energy and biosynthetic intermediates, in order to support their growth and invasiveness. However, their high proliferation rate often generates regions that are not sufficiently oxygenated. Therefore, their carbohydrate metabolism has to rely mostly on a glycolytic process that is uncoupled from oxidative phosphorylation. This metabolic switch, also known as the “Warburg Effect”, constitutes a fundamental adaptation of the tumor cells to a relatively hostile environment, and supports the evolution of aggressive and metastatic phenotypes. As a result, tumor glycolysis may constitute an attractive target for cancer therapy. This approach has often raised concerns that anti-glycolytic agents may cause serious side effects on normal cells. Actually, the key for a selective action against cancer cells can be found in their hyperbolic addiction to glycolysis, which may be exploited to generate new anti-cancer drugs showing minimal toxicity. In fact, there is growing evidence that supports many glycolytic enzymes and transporters as suitable candidate targets for cancer therapy. Herein we review some of the most relevant anti-glycolytic agents that have been investigated so far for the treatment of cancer.

Angiogenesis revisited – role and therapeutic potential of targeting endothelial metabolism

“…(Granchi and Minutolo, 2012). The incomplete and transient decrease in glycolysis by PFKFB3 blockade with 3PO, however, induces endothelial cell quiescence without causing extensive damage, highlighting a paradigm-shifting strategy in anti-angiogenic treatment (Fig.…”

Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease

“…Dependency on aerobic glycolysis renders cancer and possibly cyst-derived cells more susceptible to death than control cells after glucose deprivation or interference with glycolysis (163)(164)(165). Observations that Pkd1 −/− mouse embryonic fibroblasts (MEFs) acidify culture medium faster than wild-type cells, have lower glucose and higher lactate and ATP concentrations, and have increased transcription of key glycolytic enzymes suggested a shift of energy metabolism toward aerobic glycolysis in PKD (163).…”

The Impact of the Unfolded Protein Response and the Hexosamine Biosynthetic Pathway on Glycosylation

“…However, there are a number of compounds that inhibit various stages of the glycolytic pathway, and these are currently in development as potential cancer therapeutics. 133,134 Some of these molecules have had a measure of success in preclinical development and some have had modest success in early clinical trials. For example, pyruvate analog 3-bromopyruvate has recently entered into clinical phase I testing.…”