The metabolic properties of cancer cells diverge significantly from those of normal cells. Energy production in cancer cells is abnormally dependent on aerobic glycolysis. In addition to the dependency on glycolysis, cancer cells have other atypical metabolic characteristics such as increased fatty acid synthesis and increased rates of glutamine metabolism. Emerging evidence shows that many features characteristic to cancer cells, such as dysregulated Warburg-like glucose metabolism, fatty acid synthesis and glutaminolysis are linked to therapeutic resistance in cancer treatment. Therefore, targeting cellular metabolism may improve the response to cancer therapeutics and the combination of chemotherapeutic drugs with cellular metabolism inhibitors may represent a promising strategy to overcome drug resistance in cancer therapy. Recently, several review articles have summarized the anticancer targets in the metabolic pathways and metabolic inhibitor-induced cell death pathways, however, the dysregulated metabolism in therapeutic resistance, which is a highly clinical relevant area in cancer metabolism research, has not been specifically addressed. From this unique angle, this review article will discuss the relationship between dysregulated cellular metabolism and cancer drug resistance and how targeting of metabolic enzymes, such as glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase A, pyruvate dehydrogenase kinase, fatty acid synthase and glutaminase can enhance the efficacy of common therapeutic agents or overcome resistance to chemotherapy or radiotherapy.

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Targeting cellular metabolism to improve cancer therapeutics

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.

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Tumor glycolysis as a target for cancer therapy: progress and prospects.

In recent years there has been a growing interest among cancer biologists in cancer metabolism. This Review summarizes past and recent advances in our understanding of the reprogramming of glucose metabolism in cancer cells, which is mediated by oncogenic drivers and by the undifferentiated character of cancer cells. The reprogrammed glucose metabolism in cancer cells is required to fulfil anabolic demands. This Review discusses the possibility of exploiting the reprogrammed glucose metabolism for therapeutic approaches that selectively target cancer cells.

Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?

Malignant cells exhibit metabolic changes, when compared to their normal counterparts, owing to both genetic and epigenetic alterations. Although such a metabolic rewiring has recently been indicated as yet another general hallmark of cancer, accumulating evidence suggests that the metabolic alterations of each neoplasm represent a molecular signature that intimately accompanies and allows for different facets of malignant transformation. During the past decade, targeting cancer metabolism has emerged as a promising strategy for the development of selective antineoplastic agents. Here, we discuss the intimate relationship between metabolism and malignancy, focusing on strategies through which this central aspect of tumour biology might be turned into cancer's Achilles heel.

Metabolic targets for cancer therapy

Solute carrier (SLC) transporters - a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes - have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets.

/pdf/slc-transporters-as-therapeutic-targets-emerging-tymmh6ta8e.pdf

SLC transporters as therapeutic targets: emerging opportunities

The functional and therapeutic importance of the Warburg effect is increasingly recognized, and glycolysis has become a target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by a glucose deprivation-like mechanism. We hypothesized that the compounds target Glut1 and are efficacious in vivo as anticancer agents. Here, we report that a novel representative compound WZB117 not only inhibited cell growth in cancer cell lines but also inhibited cancer growth in a nude mouse model. Daily intraperitoneal injection of WZB117 at 10 mg/kg resulted in a more than 70% reduction in the size of human lung cancer of A549 cell origin. Mechanism studies showed that WZB117 inhibited glucose transport in human red blood cells (RBC), which express Glut1 as their sole glucose transporter. Cancer cell treatment with WZB117 led to decreases in levels of Glut1 protein, intracellular ATP, and glycolytic enzymes. All these changes were followed by increase in ATP-sensing enzyme AMP-activated protein kinase (AMPK) and declines in cyclin E2 as well as phosphorylated retinoblastoma, resulting in cell-cycle arrest, senescence, and necrosis. Addition of extracellular ATP rescued compound-treated cancer cells, suggesting that the reduction of intracellular ATP plays an important role in the anticancer mechanism of the molecule. Senescence induction and the essential role of ATP were reported for the first time in Glut1 inhibitor-treated cancer cells. Thus, WZB117 is a prototype for further development of anticancer therapeutics targeting Glut1-mediated glucose transport and glucose metabolism.

https://mct.aacrjournals.org/content/molcanther/11/8/1672.full.pdf

A Small-Molecule Inhibitor of Glucose Transporter 1 Downregulates Glycolysis, Induces Cell-Cycle Arrest, and Inhibits Cancer Cell Growth In Vitro and In Vivo

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL

Increased dependence on glycolysis and glucose metabolism, known as the Warburg effect, is a near-universal hallmark of cancer. The functional and therapeutic importance of the effect has been increasingly recognized and glycolysis has become a new target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by using a glucose deprivation-like mechanism. Based on these and other results, we hypothesized that the compounds inhibit cancer growth by targeting Glut1 and they are efficacious in vivo as anticancer agents. Here we report that the representative and novel compound WZB117 not only inhibited cancer cell growth in multiple cancer cell lines but also inhibited cancer growth in a nude mouse model. Daily intraperitoneal (ip) injection of WZB117 at a dose of 10 mg/kg resulted in an over 70% reduction in the average size of xenografted tumor of human lung cancer A549 cell origin. Compound target study showed that WZB117 inhibited glucose transport in human red blood cells (RBC) and RBC-derived vesicles, both of which express Glut1 as their sole glucose transporter. Docking studies of WZB117-Glut1 interaction also demonstrate and support the binding of WZB117 to Glut1. Mechanism studies using multiple cancer cell lines revealed that treatment of WZB117 led to an induction of glycolytic enzymes, such as hexokinase, PKM2 and PGAM1; and then a decline of glycolysis as indicated by reduced lactate production with changes in Akt, AMPK and mTOR, protein factors in energy sensitive signaling pathways. These resulted in ER stress, followed by cell cycle arrest mediated through downregulation of cyclin E and Rb. Taken together, cell cycle arrest at G1/S phase plays major roles in the WZB117-induced inhibition of cancer cell growth while apoptosis is secondary. WZB117 can serve as a prototypic compound for further development of Glut1 inhibitors into novel anticancer therapeutics targeting glucose transport and glucose metabolism.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3231. doi:1538-7445.AM2012-3231

Abstract 3231: A small molecule inhibitor of glucose transporter 1 (Glut1) down-regulates glycolysis, induces cell cycle arrest, and inhibits cancer cell growthin vitroandin vivo

Juan Ding

Papers

A Small-Molecule Inhibitor of Glucose Transporter 1 Downregulates Glycolysis, Induces Cell-Cycle Arrest, and Inhibits Cancer Cell Growth In Vitro and In Vivo

Abstract 3231: A small molecule inhibitor of glucose transporter 1 (Glut1) down-regulates glycolysis, induces cell cycle arrest, and inhibits cancer cell growthin vitroandin vivo