Inhibiting Gene "Silencing" to Inhibit Cancer

Researchers at the Fred Hutchinson Cancer Research Center report that they have discovered a chemical compound that reverses a process called "silencing," in which genes or chromosomal regions are shut off.

Such inhibitors of gene silencing could have significant applications for treating a variety of cancers, including certain forms of breast cancer which result from genetic abnormalities.

Writing in the Proceedings of the National Academy of Sciences, Dr. Antonio Bedalov and colleagues noted that in addition to treating certain cancers, compounds that block gene silencing also may be effective against sickle-cell anemia.

The researchers focused their drug search on one target, a silencing protein called Sir2. While the protein has been studied extensively in yeast, it has been found in many different organisms. Human cells, for example, have seven such genes.

Sir2 is an attractive drug target because the protein has recently been found to influence the function of p53, an important tumor-suppressor protein which, when defective, can increase cancer risk.

The researchers screened 6,000 chemical compounds and finally identified one that effectively blocked all of Sir2's silencing capabilities. The compound's only role, in fact, appears to be to inhibit Sir2 function, which makes the drug highly specific to its target - an attractive feature for a drug in terms of increasing its effectiveness and decreasing side effects.

The researchers found that this compound, which they named splitomicin, appears to be effective in sensitizing human cells to DNA-damaging agents, which would increase the effectiveness of cancer chemotherapy since many anti-cancer drugs inflict DNA damage. Another potential clinical application may be activating silent tumor-suppressor genes to fight cancer growth.

"Our hope is that this chemical/genetics approach can lead to quicker development of treatments for people with cancer and other diseases," said Bedalov.

SOURCES:
Fred Hutchinson Cancer Research Center (http://www.fhcrc.org)
Proceedings of the National Academy of Sciences, December 18, 2001

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