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Small, Smac-like molecule encourages death of cancer cells

DALLAS Sept. 2, 2004 Researchers at UT Southwestern Medical Center at Dallas have developed a small molecule that mimics the action of a key "death-promoting" protein in cells, a finding that could lead to more effective cancer therapies with fewer side effects.

In the Sept. 3 issue of the journal Science, the researchers report on this new compound and how it behaves like the cellular protein Smac, a molecule that lifts barriers to cell death. Dr. Xiaodong Wang, professor of biochemistry and one of the authors of the Science paper, discovered Smac in 2000.

"Every cell in our body has a self-destruction apparatus that becomes activated when a cell needs to be terminated," Dr. Wang said. "The Smac protein is one component of this normal cell-suicide process, called apoptosis."

Apoptosis, for example, is required for the removal of webbing between the toes and fingers of a developing fetus, as well as for the elimination of surplus neurons during the development of the human brain.

In healthy cells, Smac is sequestered within cell compartments called mitochondria, where the protein resides until mitochondria receive signals to release it. Smac then interacts with other molecules called inhibitor-of-apoptosis proteins (IAPs), which, if not countered by Smac, will keep the cell alive and growing.

In cancer cells, IAPs tend to be overexpressed, and the signals that tell mitochondria to release Smac are often defective. That's why the UT Southwestern-developed Smac mimic, which can enter the cytoplasm of cells unhindered, is an important step in developing new cancer therapies, said Dr. Patrick Harran, associate professor of biochemistry and an author of the study.

The compound, which so far has only been tested on cells in culture, does not appear to harm normal cells, just cancer cells, said Dr. Wang, who is a Howard Hughes Medical Institute investigator and holds the George L. MacGregor Distinguished Chair in Biomedical
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Contact: Amanda Siegfried
Amanda.siegfried@utsouthwestern.edu
214-648-3404
UT Southwestern Medical Center
2-Sep-2004


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