Altered energy metabolism is a biochemical fingerprint of cancer cells that represents one of the “hallmarks of cancer”. This metabolic phenotype is characterized by preferential dependence on glycolysis (the process of conversion of glucose into pyruvate followed by lactate production) for energy production in an oxygen-independent manner. Although glycolysis is less efficient than oxidative phosphorylation in the net yield of adenosine triphosphate (ATP), cancer cells adapt to this mathematical disadvantage by increased glucose up-take, which in turn facilitates a higher rate of glycolysis. Apart from providing cellular energy, the metabolic intermediates of glycolysis also play a pivotal role in macromolecular biosynthesis, thus conferring selective advantage to cancer cells under diminished nutrient supply. Accumulating data also indicate that intracellular ATP is a critical determinant of chemoresistance. Under hypoxic conditions where glycolysis remains the predominant energy producing pathway sensitizing cancer cells would require intracellular depletion of ATP by inhibition of glycolysis. Together, the oncogenic regulation of glycolysis and multifaceted roles of glycolytic components underscore the biological significance of tumor glycolysis. Thus targeting glycolysis remains attractive for therapeutic intervention. Several preclinical investigations have indeed demonstrated the effectiveness of this therapeutic approach thereby supporting its scientific rationale. Recent reviews have provided a wealth of information on the biochemical targets of glycolysis and their inhibitors. The objective of this review is to present the most recent research on the cancer-specific role of glycolytic enzymes including their non-glycolytic functions in order to explore the potential for therapeutic opportunities. Further, we discuss the translational potential of emerging drug candidates in light of technical advances in treatment modalities such as image-guided targeted delivery of cancer therapeutics.

Aerobic glycolysis is the process of oxidation of glucose into pyruvate followed by lactate production under normoxic condition. Distinctive from its anaerobic counterpart (i.e. glycolysis that occurs under hypoxia), aerobic glycolysis is frequently witnessed in cancers, popularly known as the "Warburg effect", and it is one of the earliest known evidences of metabolic alteration in neoplasms. Intracellularly, aerobic glycolysis circumvents mitochondrial oxidative phosphorylation (OxPhos), facilitating an increased rate of glucose hydrolysis. This in turn enables cancer cells to successfully compete with normal cells for glucose uptake in order to maintain uninterrupted growth. In addition, evading OxPhos mitigates excessive generation/accumulation of reactive oxygen species that otherwise may be deleterious to cells. Emerging data indicate that aerobic glycolysis in cancer also promotes glutaminolysis to satisfy the precursor requirements of certain biosynthetic processes (e.g. nucleic acids). Next, the metabolic intermediates of aerobic glycolysis also feed the pentose phosphate pathway (PPP) to facilitate macromolecular biosynthesis necessary for cancer cell growth and proliferation. Extracellularly, the extrusion of the end-product of aerobic glycolysis, i.e. lactate, alters the tumor microenvironment, and impacts cancer-associated cells. Collectively, accumulating data unequivocally demonstrate that aerobic glycolysis implicates myriad of molecular and functional processes to support cancer progression. This review, in the light of recent research, dissects the molecular intricacies of its regulation, and also deliberates the emerging paradigms to target aerobic glycolysis in cancer therapy.

The pathogenesis of malarial anemia is multifactorial, and the mechanisms responsible for its high mortality are poorly understood. Studies indicate that host mediators produced during malaria infection may suppress erythroid progenitor development (Miller, K.L., J.C. Schooley, K.L. Smith, B. Kullgren, L.J. Mahlmann, and P.H. Silverman. 1989. Exp. Hematol. 17:379–385; Yap, G.S., and M.M. Stevenson. 1991. Ann. NY Acad. Sci. 628:279–281). We describe an intrinsic role for macrophage migration inhibitory factor (MIF) in the development of the anemic complications and bone marrow suppression that are associated with malaria infection. At concentrations found in the circulation of malaria-infected patients, MIF suppressed erythropoietin-dependent erythroid colony formation. MIF synergized with tumor necrosis factor and γ interferon, which are known antagonists of hematopoiesis, even when these cytokines were present in subinhibitory concentrations. MIF inhibited erythroid differentiation and hemoglobin production, and it antagonized the pattern of mitogen-activated protein kinase phosphorylation that normally occurs during erythroid progenitor differentiation. Infection of MIF knockout mice with Plasmodium chabaudi resulted in less severe anemia, improved erythroid progenitor development, and increased survival compared with wild-type controls. We also found that human mononuclear cells carrying highly expressed MIF alleles produced more MIF when stimulated with the malarial product hemozoin compared with cells carrying low expression MIF alleles. These data suggest that polymorphisms at the MIF locus may influence the levels of MIF produced in the innate response to malaria infection and the likelihood of anemic complications.

The pyruvate analog, 3-bromopyruvate, is an alkylating agent and a potent inhibitor of glycolysis. This antiglycolytic property of 3-bromopyruvate has recently been exploited to target cancer cells, as most tumors depend on glycolysis for their energy requirements. The anticancer effect of 3-bromopyruvate is achieved by depleting intracellular energy (ATP) resulting in tumor cell death. In this review, we will discuss the principal mechanism of action and primary targets of 3-bromopyruvate, and report the impressive antitumor effects of 3-bromopyruvate in multiple animal tumor models. We describe that the primary mechanism of 3-bromopyruvate is via preferential alkylation of GAPDH and that 3- bromopyruvate mediated cell death is linked to generation of free radicals. Research in our laboratory also revealed that 3- bromopyruvate induces endoplasmic reticulum stress, inhibits global protein synthesis further contributing to cancer cell death. Therefore, these and other studies reveal the tremendous potential of 3-bromopyruvate as an anticancer agent.

Hepatocellular carcinoma (HCC) is one of the most highly lethal malignancies ranking as the third leading-cause of cancer-related death worldwide. Although surgical resection and transplantation are effective curative therapies, very few patients qualify for such treatments due to the advanced stage of the disease at diagnosis. In this context, loco-regional therapies provide a viable therapeutic alternative with minimal systemic toxicity. However, as chemoresistance and tumor recurrence negatively impact the success of therapy resulting in poorer patient outcomes it is imperative to identify new molecular target(s) in cancer cells that could be effectively targeted by novel agents. Recent research has demonstrated that proliferation in HCC is associated with increased glucose metabolism. The glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a multifunctional protein primarily recognized for its role in glucose metabolism, has already been shown to affect the proliferative potential of cancer cells. In human HCC, the increased expression of GAPDH is invariably associated with enhanced glycolytic capacity facilitating tumor progression. Though it is not yet known whether GAPDH up-regulation contributes to tumorigenesis sensu stricto, emerging evidence points to the existence of a link between GAPDH up-regulation and the promotion of survival mechanisms in cancer cells as well as chemoresistance. The involvement of GAPDH in several hepatocarcinogenic mechanisms (e.g. viral hepatitis, metabolic alterations) and its sensitivity to a new class of prospective anticancer agents prompted us to review the current understanding of the therapeutic potential of targeting GAPDH in HCC.