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The Anticancer Activity of Monosaccharides: Perspectives and Outlooks - PubMed

  • ️Mon Jan 01 2024

Review

The Anticancer Activity of Monosaccharides: Perspectives and Outlooks

Niamh McCallum et al. Cancers (Basel). 2024.

Abstract

A major hallmark of cancer is the reprogramming of cellular metabolism from oxidative phosphorylation (OXPHOS) to glycolysis, a phenomenon known as the Warburg effect. To sustain high rates of glycolysis, cancer cells overexpress GLUT transporters and glycolytic enzymes, allowing for the enhanced uptake and consumption of glucose. The Warburg effect may be exploited in the treatment of cancer; certain epimers and derivatives of glucose can enter cancer cells and inhibit glycolytic enzymes, stunting metabolism and causing cell death. These include common dietary monosaccharides (ᴅ-mannose, ᴅ-galactose, ᴅ-glucosamine, ʟ-fucose), as well as some rare monosaccharides (xylitol, ᴅ-allose, ʟ-sorbose, ʟ-rhamnose). This article reviews the literature on these sugars in in vitro and in vivo models of cancer, discussing their mechanisms of cytotoxicity. In addition to this, the anticancer potential of some synthetically modified monosaccharides, such as 2-deoxy-ᴅ-glucose and its acetylated and halogenated derivatives, is reviewed. Further, this article reviews how certain monosaccharides can be used in combination with anticancer drugs to potentiate conventional chemotherapies and to help overcome chemoresistance. Finally, the limitations of administering two separate agents, a sugar and a chemotherapeutic drug, are discussed. The potential of the glycoconjugation of classical or repurposed chemotherapy drugs as a solution to these limitations is reviewed.

Keywords: anticancer drugs; antitumour therapy; glycolysis; monosaccharides; natural products; sugars.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1

Schematic representation of the differences in metabolism between healthy cells and cancer cells. (a) In the presence of oxygen, healthy cells undergo oxidative phosphorylation (OXPHOS) to generate energy. Meanwhile, under hypoxia, normal cells undertake anaerobic glycolysis for metabolism, which generates lactate as the byproduct. (b) On the other hand, cancer cells preferentially undertake glycolysis for metabolism under both hypoxic and normoxic conditions, a phenomenon known as the Warburg effect. Created with Biorender.com.

Figure 2
Figure 2

Haworth projections of the hemiacetal form of some common monosaccharides.

Figure 3
Figure 3

Schematic representing the effects of mannose loading on PMI processing capacity and hence metabolism. When cells are treated with mannose at doses greater than the processing capacity of PMI, less mannose is converted to fructose-6-phosphate for use in glycolysis and so metabolism is suppressed, and cells are starved of energy. Created with Biorender.com.

Figure 4
Figure 4

Haworth projections of the hemiacetal form of some rare monosaccharides.

Figure 5
Figure 5

Haworth projections of the hemiacetal forms of some structurally modified monosaccharides.

Figure 6
Figure 6

Summary of the effects of 2-DG under normoxia and hypoxia. (a) Under normoxic conditions, 2-DG inhibits glycolysis, reducing ATP levels, leading to apoptosis. Further, 2-DG inhibits glycosylation, which leads to ER stress and autophagy. Finally, 2-DG inhibits the pentose phosphate pathway (PPP), which results in oxidative stress. (b) Under hypoxic conditions, 2-DG significantly impairs glycolysis, reducing ATP levels, leading directly to cell death and the inhibition of autophagy. Upwards pointing arrows signify upregulation of a process or increased levels of a particular molecule, whilst down pointing arrows signify downregulation of a process or decreased levels of a particular molecule.

Figure 7
Figure 7

Structure of the glucose-conjugated drug, glufosfamide, compared to the structure of its parent compound, ifosfamide.

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