Inhibit Glycolysis to Starve Tumour Cells

published: 30 Nov 2011 (11:47)

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The multi-system disease called Tuberous Sclerosis is caused by mutations in tumour suppressor genes TSC1 and TSC2. These are gene codes for proteins called hamartin and tuberin which regulate the growth and differentiation of cells in a body and thus suppress the growth of tumours. Mutations in these genes result in non-malignant tumour growths in vital body organs like brain, heart, kidneys and lungs which may lead to multi organ failure. Some of the major symptoms include seizures, delayed development, psychological problems, and skin anomalies along with kidney and lung disorders.

According to a new research published in the open access journal, Cell and Bioscience by BioMed Central, 2-deoxyglucose can be used to restrict the growth of such TSC related tumours which require glucose for their proliferation. 2-deoxyglucose is a unique molecule that blocks the metabolism of glucose and at the same time does not restrict dietary carbohydrates. Under normal circumstances, the genes called TSC1 and TSC 2 inhibit the pathway for signalling mTOR but if mutations occur in these genes, normal functioning of the genes as well their targets is hampered. Cell growth is then carried out by the unregulated mTORC1 which also controls glycolysis.

The current treatment modality for tuberous sclerosis is a drug called Rapamycin which blocks mTORC1 complex. Apart from being anti-neoplastic, Rapamycin has an immunosuppressive action as well. This immunosuppressive nature leads to some undesirable side effects when used for a longer duration. A study conducted by researchers of Washington University closely examined the potential of cell proliferation blockage by decreasing the amount of glycolysis.

In mice, some TSC2-negative tumours were kept on an unrestricted carbohydrate free diet while others were kept on a western-style diet. It was inferred that the former had a much larger growth rate as compared to the mice kept on a western diet. Nevertheless, the molecule 2-deoxyglucose, which is known for its glycolytic action reduced the tumour size in mice irrespective of its diet.

Professor Raymond S. Yeung, the lead researcher explained that when treated with 2-DG, the tumour cells showed a significant fall in their growth. The rate of division of tumour cells further decreased when 2-DG was combined with a diet rich in carbohydrates. The synergistic effect of 2-DG and western diet has a detrimental effect on the tumour growth, thus starving the tumour cells. Under this condition, tumour cells exhibit the lowest levels of serum glucose. On the other hand, diet rich in fats and devoid of carbohydrates provides free fatty acids to carry on the growth of tumour cells. A few fatty acids used for the experiment proved to be toxic to the proliferating tumour cells. This toxic nature of some fatty acids causes liquefaction necrosis which further adds on to the tumour mass.

Unique molecules like 2-DG have shown to have a greater potential in inhibiting TSC-2 negative tumours by curbing the rate of glycolysis. Such studies may prove its worth in treatment of deadly cancers like prostate.

Xiuyun Jiang, Heidi L Kenerson and Raymond S Yeung, Glucose deprivation in tuberous sclerosis complex-related tumors, Cell & Bioscience, 2011, 1:34 doi:10.1186/2045-3701-1-34

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