Small-Molecule Inhibition of Glucose Transporters GLUT-1-4, 2020, Reckzeh & Waldmann

[SNT Gatchaman]

Small-Molecule Inhibition of Glucose Transporters GLUT-1-4
Elena S Reckzeh, Herbert Waldmann

Glucose addiction is observed in cancer and other diseases that are associated with hyperproliferation. The development of compounds that restrict glucose supply and decrease glycolysis has great potential for the development of new therapeutic approaches. Addressing facilitative glucose transporters (GLUTs), which are often upregulated in glucose-dependent cells, is therefore of particular interest. This article reviews a selection of potent, isoform-selective GLUT inhibitors and their biological characterization. Potential therapeutic applications of GLUT inhibitors in oncology and other diseases that are linked to glucose addiction are discussed.

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[SNT Gatchaman]

Detailed review article, posted for background on cellular fuel starvation as a potential mechanism in ME energy impairment.

The altered energy metabolism of cancer was first investigated by Otto Warburg in 1924. He observed that cancer cells perform glycolysis and ferment the thereby generated pyruvate to lactate irrespective of oxygen availability. This phenomenon was termed aerobic glycolysis, or the Warburg effect, and yields about 4 mol ATP per mol glucose. Nonmalignant cells fuel pyruvate into the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in the presence of oxygen in order to generate approximately 36mol ATP per mol absorbed glucose.

Aerobic glycolysis and increased glucose dependence are also characteristic for inflammatory diseases. CD4+ T cells switch from fatty acid b oxidation in the resting state to aerobic glycolysis after activation. Interestingly, GLUT-1-deficient CD4+ T cells were unable to grow, proliferate, survive and differentiate to T effector cells after activation. T cells that upregulate aerobic glycolysis are involved in the establishment of inflammatory bowel disease, graft-versus-host disease and systemic lupus erythematosus.

Hyperplasia-associated diseases, such as psoriasis and fibrosis, exhibit uncontrolled cell proliferation and increased GLUT-1 levels, offering potential for modulation by treatment with glucose import inhibitors.

Viral infections also lead to an adaptation of the energy metabolism of the host cells toward aerobic glycolysis.