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The good and bad side of anti-cancer compounds
Date:4/10/2008

Compounds known as HDAC inhibitors exhibit cancer-killing activities in cultured cells. While they are currently being tested as anti-cancer agents in clinical trials, just how they execute their effects is unclear.

In a pair of recent papers, Vanderbilt-Ingram Cancer Center investigators provide a potential mechanism by which HDAC inhibitors specifically damage cancer cells and offer clues about possible adverse effects of these compounds findings with important implications for their clinical use as cancer therapies.

Scott Hiebert, Ph.D., professor of Biochemistry and Medicine, and colleagues initially set out to study how chromosomal translocations which happen when chromosomes break and rejoin, creating new genes at the breakpoints cause acute leukemias.

He previously had found that a chromosomal translocation common in acute myeloid leukemias led to the formation of a new protein, a mutant transcription factor, that actively turned genes off. Enzymes known as histone deacetylases (HDACs) helped the mutant protein turn genes off by stabilizing the tightly coiled structure of DNA in chromosomes, making it inaccessible to proteins that transcribe DNA.

We thought that if we could inhibit these HDACs, we could turn the genes back on and cure leukemia, Hiebert explained.

While there are at least 17 different HDACs, Hieberts work suggested that one in particular, called HDAC3, might be the critical HDAC in triggering acute leukemia.

To investigate the effects of inhibiting HDAC3, Hiebert and colleagues genetically engineered mice lacking the protein. However, the mice died before birth. Even when grown in cell culture, mouse cells lacking HDAC3 died.

The question is: why are they dying? And what we found was kind of surprising, he said.

In the April 11 issue of Molecular Cell, Hiebert and colleagues report that these cells die because they cant repair the DNA damage that occurs natur
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Contact: Dagny Stuart McMillin
dagny.stuart@Vanderbilt.Edu
615-322-4747
Vanderbilt University Medical Center
Source:Eurekalert

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