Tuberous sclerosis is a rare genetic disease which results from the mutation in one of two tumor suppressor genes, TSC1 or TSC2. The condition causes non-malignant tumors to grow in the brain and other vital organs throughout the body and skin and can cause serious damage. Tumors in the brain might cause seizures, and tumors in the liver, heart of kidney can disrupt normal function and may cause them to fail. However, according to a new study published in BioMed Central’s open access journal Cell and Bioscience, the growth of glucose-dependent TSC-related tumors can be restricted by 2-deoxyglucose, which blocks glucose metabolism without restricting dietary carbohydrates.

Usually the mTOR signaling pathway is restricted by TSC1 and TSC2, but genes that are mutated and no longer work cause unregulated mTORC1 which powers cell growth and glucolysis.

At present, the drug rapamycin is used to treat tuberous sclerosis by obstructing mTORC1. However, rapamycin is an immunosuppressant and can have considerable adverse effects, especially when used for long periods. A team of investigators, led by Prof Yeung from the University of Washington, examined the possibility of blocking cell proliferation by directly reducing glycolysis.

They discovered that mice with TSC2-negative tumors who were kept on an unrestricted carbohydrate-free diet grew bigger compared to mice who were kept on a western-style diet. However, on both diets, the glucose analogue, 2-deoxyglucose (2DG), reduced tumor size.

Prof. Yeung said:

“Treatment with 2DG significantly reduced the rate at which the tumor cells divided, especially when paired with a diet which contained carbohydrates. This combination of 2DG and a western-style diet imposed the greatest energy stress on the tumors and correlated with the lowest levels of serum glucose.

On the other hand, while the carbohydrate-free (and high-fat) diet provided enough free fatty acids to sustain tumor growth, some of the saturated fatty acids appeared toxic to the tumor cells. This in turn led to an accumulation of liquefied, necrotic materials that contributed to greater tumor size.”

Compounds such as 2-deoxyglucose are able to prevent TSC2-negative tumor growth by restricting glycolysis in a way not observed by reducing dietary glucose.

At present, researchers are testing 2DG for use in prostate cancer. This, together with other novel metabolic interventions hold promise for the future of cancer treatment.

Written by Grace Rattue