Researchers Discover Drug that Starves Cancer Cells of their Glucose Energy Supply

by Dr Sam Girgis on August 4, 2011

Oncogenesis occurs in cancer cells by several mechanisms, but the most common involves mutation of oncogenes or tumor suppressor genes.  In this way, cancer cells gain a proliferative advantage over normal cells and can outgrow the normal tissues in an organism and metastasize to distant sites.  Cancer cells also have key metabolic differences, when compared to normal cells, that allows them to grow at a much faster and accelerated rate.  Malignant cancer cells typically have metabolic rate that are up to 200 times faster than the normal tissue that they originate from.  In order for cancer cells to proliferate at such high rates and maintain a metabolic rate that is so high, they need a constant supply of energy.  Cancer cells accomplish this by producing energy by glycolysis followed by lactic acid fermentation in the cytosol.  In normal cells, metabolism occurs by a much slower process of glycolysis that occurs by oxidation of pyruvate in the mitochondria.  This difference in glucose metabolism was described by Dr. Otto Warburg as the fundamental cause of cancer and now bears his name as the Warburg effect.  Researchers lead by Dr. Amato Giaccia have discovered a drug that takes advance of the Warburg effect by starving cancer cells of their glucose energy supply.  Their research results were published online in the journal Science Translational Medicine.  The researchers used a high-throuphput chemical synthetic lethality screen to analyze 64,000 compounds for their cytotoxicity to cancer cells.  The researchers used a renal cell carcinoma (RCC) cell line that lacks the von Hippel-Lindau (VHL) tumor suppressor gene.  This RCC cell line is dependent on aerobic glycolysis for its metabolism, as described in the Warburg effect.  Using their screening process, the researchers identified a drug termed STF-31 which specifically targets glucose uptake through the glucose transporter GLUT1.  By inhibiting glucose uptake by the RCC cell line, STF-31 starves the cancer cells of their energy supply and specifically targets the high metabolic rate described by the Warburg phenomenon.  In addition, the researchers show that STF-31 exerts its cytotoxicity in a manner that is dependent on the lack of the VHL tumor suppressor gene.  In RCC cells that lack the VHL tumor suppressor gene, GLUT1 is upregulated and more highly expressed.  In this manner, STF-31 specifically targets malignant cells while allowing normal cells to remain unaffected by its toxicity.  The researchers were also able to assess glucose uptake in an in vivo mouse model after treatment with STF-31 by the use of fluorodeoxyglucose positron emission tomography (PET) scanning.  Since PET scanning is commonly used in humans to assess tumor activity, it can be used to assess STF-31 activity in the treatment of human cancers.  The authors wrote, “In this report, we identify a class of compounds that impair glucose transport, resulting in specific killing of renal carcinoma cells… subsequent experiments illustrate that STF-31 is generally synthetically lethal to cancer cells that have high GLUT1 levels and require glycolysis. It is likely that a number of other cancer types have additional genetic or epigenetic alterations that make them highly dependent on aerobic glycolysis for energy production and therefore sensitive to STF-31… Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy”.  There are several drugs that specifically target the increased glucose metabolism of malignant cells that are in preclinical trials for the treatment of cancer.  Based on these results, STF-31 could also be an excellent candidate for further research as a chemotherapeutic agent.

Reference:

Denise A. Chan et al. “Targeting GLUT1 and the Warburg Effect in Renal Cell Carcinoma by Chemical Synthetic LethalitySci Transl Med 3 August 2011: Vol. 3, Issue 94, p. 94ra70 DOI:10.1126/scitranslmed.3002394

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