Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy
Graphical abstract
Introduction
Cancer incidence is rapidly growing with an expected increase of 70 % over the next two decades. Cancer is ranked as a leading cause of death, accounting for 13 % of all mortality worldwide (GLOBOCAN 2018 database) [1]. Metabolism of cancer cells is different from that of normal cells, which allows them to sustain a high rate of proliferation and resist signals of apoptosis [2]. Normally, cells utilize multiple metabolic pathways to produce energy depending on the availability of metabolites and biosynthetic requirements for cellular function. Cells typically use glycolysis to convert glucose into pyruvate in the cytosol. The pyruvate is further metabolized in the mitochondria by oxidative phosphorylation (OxPhos) through the tricarboxylic acid (TCA) cycle and electron transport chain (ETC), to produce the energy-storing adenosine triphosphate (ATP). Under hypoxic conditions, cells can utilize anaerobic glycolysis, and converts pyruvate into lactate, producing much less amount of ATP, but at a faster rate [3]. Mitochondrial oxidation of one glucose molecule yields 36 molecules of ATP, while its metabolism to lactate by glycolysis produces only 2 ATP molecules. Under aerobic conditions, cells can also utilize fatty-acid oxidation (called beta-oxidation) or glutamine oxidation, if these metabolites are available [3].
Tumor cells, unlike normal cells, depend largely on glycolysis for producing energy even in the presence of adequate levels of oxygen, a process termed aerobic glycolysis [4]. Thus, inhibition of glycolytic pathways has the potential to provide an effective approach to cancer research aiming to develop new targeted anticancer agents. This approach has been proven effective in suppressing tumor progression, and several of these glycolytic inhibitors are currently under investigation in preclinical and clinical studies with promising results [[5], [6], [7]]. This review will present the most recent data on the emerging candidate agents targeting glycolytic enzymes and intermediates to be useful in cancer therapy.
Section snippets
Tumor glucose metabolism and Warburg effect
Cancer progression involves an inappropriate proliferation of cells, which have enhanced abilities for energy production to resist metabolic stresses [8]. Tumor cell metabolism is reprogrammed in favor of aerobic glycolysis despite the presence of plentiful oxygen [9]. This observation was first reported many decades ago by the German scientist Otto Warburg and is thus referred to as the “Warburg effect” [10]. This metabolic alteration to a high glycolysis rate has been observed in a variety of
Dual metabolic phenotype and hybrid state
The glycolytic phenotype is known to be expressed by many cancers [21], but the dependence of cancer cells on such phenotype remains unclear. It has been demonstrated cancer cell death can be induced by reversing the glycolytic state to OxPhos [22]. The glycolytic cancer cells can exhibit a non-glycolytic phenotype under acidic conditions by intracellular lactic acid accumulation. Lactic acidosis is a common consequence of the Warburg effect in most solid tumors [23]. Tumor cells cultured with
Reverse Warburg effect or metabolic coupling
Another type of tumor metabolism has been recently observed in certain types of cancers called the “reverse Warburg effect” or “metabolic coupling” which have high mitochondrial respiration and low glycolysis rate [40]. In this type, the tumor cells and adjacent stromal fibroblasts form a two-compartment model of cancer metabolism, where aerobic glycolysis occurs in fibroblasts, and the generated metabolites are transferred to malignant cells, to fuel the TCA cycle and maintain ATP generation [
Warburg effect and tumor acidosis
The microenvironment of solid tumors is markedly heterogenous, so tumor cells tend to increase their uptake of glucose to maintain energy production [13]. Increased glycolysis and decreased mitochondrial oxidation lead to increased formation of lactic acid, increased glutaminolysis, increased beta-oxidation of fatty acids and activation of the pentose phosphate pathway [45]. To maintain the intracellular pH (pHi), tumor cells promptly export the excess intracellular acid load to the
Tumor glycolysis and its clinical relevance to cancer progression
The glycolysis process takes place in the cytoplasm by converting glucose into pyruvate through nine reaction steps, involving several glycolytic enzymes. First, glucose is transported into tumor cells at a high rate by glucose transporters (GLUTs), GLUT1 and sodium-glucose linked transporter 1 (SGLT1) which are overexpressed in most cancers [50]. Glucose is phosphorylated into glucose-6-phosphate by hexokinase (HK), a rate-limiting step that provides direct feedback inhibition to preserve
Non-glycolytic functions of glycolytic enzymes and metabolic intermediates
Many glycolytic enzymes have also important roles in several non-glycolytic processes involved in cellular functions that support cancer cell survival and growth [84]. For instance, the mitochondrial membrane-bound HK2 can antagonize the proapoptotic pathway in cancer cells [85]. Also, HK2 acting as a nuclear enzyme is involved in transcriptional regulation of some nuclear proteins [84]. Similarly, GAPDH has a critical role in maintaining the cellular redox balance by catalyzing the production
Molecular regulation of tumor glycolysis
It is increasingly evident that coordinated networks of signaling pathways regulate reprogramming of cancer cells to balance their metabolic state, supporting tumor growth and stress resistance. Several studies have demonstrated the affection of cancer cell metabolism by many regulators including protooncogenes (e.g. Myc), transcription factors (e.g. HIF-1), signaling pathways (e.g. PI3K/Akt/mTOR), and tumor suppressors (e.g. p53) [97]. The c-Myc is a transcription factor, encoded by Myc
Targeting tumor metabolism and Glycolytic inhibitors
Recent cancer research focuses on selective inhibition of metabolic pathways to deprive cancer cells of essential metabolic needs and interfere with tumor growth. The improved understanding of aerobic glycolysis as a hallmark of cancer and underlying mechanisms may pave the way for the development of targeted metabolic agents for antiglycolytic cancer therapy [114]. There are several approaches to disrupt energy production and prevent glucose utilization by cancer cells. Indeed,
Conclusion and future perspective for metabolic cancer therapy
Although aerobic glycolysis is a known signature of cancer cells, targeting this pathway for therapy has not yet been successfully translated into clinical practice. Recently, this hallmark of cancer metabolism has become a focus of cancer research and drug discovery, aiming for the introduction of effective metabolic agents as a promising strategy to combat cancer. These candidate drugs might also sensitize tumor cells to other more effective cytotoxic therapies. Many emerging drugs have been
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
The authors declare that there is no conflict of interests.
Acknowledgments
We thank Dr. Abdul-Salam Noor Waly, Dean Faculty of Medicine, Umm Al-Qura University, Makkah, for providing access to the Saudi Digital Library.
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