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When a cell undergoes apoptosis, white blood cells called macrophages consume cell debris.

Any cancer researcher will tell you that cancer cells are frustratingly difficult to kill, and scientists at the University of Texas M.D. Anderson Cancer Center may have pinpointed one reason why.

The lead author of a new study, published in the June 30 issue of the journal Cell, is Dean G. Tang, PhD, associate professor in the M.D. Anderson Department of Carcinogensis. He says cells are "programmed" to die, in a process known as apoptosis, yet cancer cells have adapted to avoid it. Just how they're dodging the apoptosis bullet, however, is where the research of Tang and his associates comes in.

"Our observation is very intriguing because it is essentially against the dogma from the whole world," Tang says.

First of all, apoptosis is initiated when a cell is damaged beyond repair, infected by a virus or simply old. Scientists agree that apoptosis is triggered by the release of a protein called cytochrome c from mitochondria, the cell's main power generators. The cytochrome c joins up with another protein with the unmanageable name of apoptotic peptidase activating factor (APAF1) to activate enzymes that literally shred a cell to pieces. All this takes place in the cell's free pools of nucleotides, which Tang describes as being "like an ocean" where APAF1 is ready to bind with cytochrome c when the time is right. Yet these nucleotides aren't passive — their energy is necessary to the process.

Thus, some conventional cancer therapies operate on the premise that revving up a cell's nucleotides and increasing their numbers will prompt more binding of cytochrome c and APAF1, resulting in that cell-shredding process. Not necessarily so, Tang says, and, in fact, the opposite may be true.

"To make the story short, we provided convincing evidence indeed that intracellular nucleotides are critical survival factors for the cell," he says. When the researchers experimentally reduced the nucleotide levels, the cells died much faster, "even spontaneously or more so in response to chemotherapeutic drugs," he says. When the nucleotide levels were increased, the cells became much more resistant. "When the cytochrome c comes out of the mitochondria, it's essentially sequestered by the ocean of nucleotides, and this cytochrome c has no way even to recognize the nextly important protein called APAF1," he continues. The cytochrome c is literally and inefficiently searching and searching for APAF1 in a crowded environment.

Tang says that while his findings are particularly important for cancer therapy, the information could be useful for many cellular science applications. In his research, normal cell types as well several different types of cancer cells such as prostate, ovarian and breast were studied. "It's just that this survival mechanism appears to be augmented in cancer cells compared to normal cells," he says. The survival mechanism, in essence, is the cell's ability to maintain high nucleotide levels and thus slow or even halt the death process. Tang says he tested the hypothesis using in vitro as well as in vivo techniques.

Tang adds that he suspects other assay tests differed from his because most researchers use stored samples rather than fresh ones, "so the nucleotides got degraded."

What Tang's findings mean for cancer research could be far-reaching, revealing that therapies that combine increased release of cytochrome c with reduced nucleotide levels might stand the best chance of success. "That aspect has not been appreciated before," he says.

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