Such inhibitors of gene silencing could have significant applications for treating a variety of malignancies - including acute myelogenous leukemia, colon cancer and certain forms of breast cancer - all of which have genetic abnormalities that lead to inappropriate silencing of genes that are critical for healthy growth.
The finding appears in the Dec. 18 edition of the Proceedings of the National Academy of Sciences. The authors of the paper are Antonio Bedalov, M.D., Ph.D., a research associate in the Clinical Research Division; Dan Gottschling, Ph.D., a member of Basic Sciences Division; and Julian Simon, Ph.D., a member of the Clinical Research and Human Biology divisions.
In addition to treating certain cancers, compounds that block gene silencing also may be effective against sickle-cell anemia. "People with sickle-cell anemia have defective copies of the gene for the adult form of hemoglobin, but they possess a normal version of the fetal hemoglobin gene, which gets silenced early in life as part of normal development," Bedalov said. "Reversing silencing of fetal hemoglobin could potentially compensate for the lack of functioning hemoglobin in these patients." Silencing can be thought of as genetic hibernation, in which gene activity - the process of making proteins - is quiescent for long periods.
Gottschling's laboratory studies this phenomenon in yeast, a model organism that has a lot to teach about the origins of cancer. "There are many situations in which it's beneficial for a cell to silence regions of the genome," Gottschling said. "In yeast, for example, mating can't occur unless certain genes are silenced. But there are also mechanisms, both normal and abnormal, that allow the process to be reversed."
Some of the key genetic components of this silencing pathway in yeast are virtually identical to those in humans, which allows scientists to exploit the power of yeast genetics to study complex human processes. Therefore, yeast is an ideal system in which to look for anti-silencing - and anti-cancer - drugs. (The world learned of the significance of yeast as a model organism this fall when Hutchinson Center President and Director Lee Hartwell, Ph.D., was awarded the 2001 Nobel Prize in physiology or medicine. His groundbreaking use of yeast to study the mechanisms of cell division in all nucleated organisms, from yeast to frogs to humans, has had a profound impact on our understanding cancer, a disease that arises when cell division goes awry.)
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 recently the protein has been found to modulate 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, is to inhibit Sir2 function, which makes the drug highly specific to its target - an attractive feature for drug design in terms of increasing effectiveness and decreasing side effects.
Bedalov, a native of Croatia, named this compound "splitomicin" after his hometown, Split. The Hutchinson Center recently filed for patent protection for the compound.
Hutchinson Center researchers also have found splitomicin to be effective in sensitizing human cells to DNA-damaging agents, a finding that could be exploited to 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," Bedalov said.
Grants from the National Heart, Lung and Blood Institute; the National Institutes of Health; and the National Cancer Institute supported this work.
The Fred Hutchinson Cancer Research Center, home of two Nobel Prize laureates, is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Recognized internationally for its pioneering work in bone-marrow transplantation, the Center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. The Hutchinson Center is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest and is one of 37 nationwide. For more information, visit the Hutchinson Center's Web site at www.fhcrc.org.
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Proceedings of the National Academy of Sciences