SAN DIEGO — Department of Veterans Affairs (VA) researchers and colleagues have discovered a biochemical mechanism that may explain wasting syndrome, a condition that causes severe weight loss and weakness in patients with chronic inflammatory diseases and often hastens their death.
The findings, published in the December 3 issue of the European Molecular Biology Organization Journal, may lead to new drugs to ease the debilitating effects of cancer, AIDS, and other serious degenerative illnesses.
Scientists in San Diego pinpointed the biological chain of events that caused wasting in mice, then identified the same process in liver tissue from cancer patients.
They said the striking similarity between the condition in mice and humans will expedite the development of new treatments.
"When we saw that it was virtually identical in animals and humans, we were ecstatic," said the study’s senior author, Mario Chojkier, M.D., of the VA San Diego Healthcare System and the University of California, San Diego (UCSD).
"What we’ve described in animals has much greater relevance than we ever thought to human wasting syndrome. We’re optimistic this will bring hope and relief very quickly to the bedside."
Dr. Chojkier and lead author Martina Buck, Ph.D., of VA, UCSD and the Salk Institute for Biological Studies, described the steps by which tumor necrosis factor (TNF) alpha, an immune-system protein, prevents the production of albumin. Low levels of albumin, a critical protein made in the liver, is a keynote of wasting.
TNF-alpha and low albumin had for years been implicated in wasting, but the connection between the two was a mystery. Drs. Buck and Chojkier showed that TNF alpha causes oxidative stress in the liver cell and boosts the production of the free-radical gas nitric oxide. It also causes the addition of a phosphorous molecule to a protein called C/EBP beta, which normally joins DNA in the nucleus of the cell to make other proteins, such as albumin.
Central to the researchers’ finding was that this extra phosphorous causes the C/EBP beta to shuttle out of the nucleus into the cytoplasm, where transcription from the albumin gene can no longer take place.
"We found that this phosphorylation makes the C/EBP beta exit the nuclear area and go into the cytosol, where there is no DNA for it to bind with. This means it can no longer produce the protein," said Dr. Chojkier.
The researchers found several ways of stopping the downward spiral caused by TNF- alpha. One way was to treat TNF-alpha-enhanced mice with vitamin E and other antioxidants. This blocked the chain of events leading to the "nuclear export" of C/EBP beta.
"If we block oxidative stress, we normalize everything," explained Dr. Chojkier. "C/EBP beta remains in the nucleus, it contacts the DNA, and proteins are produced. Or, if we block the nitric oxide synthase activity, this also blocks the downstream cascade, and everything normalizes."
According to Dr. Chojkier, a gastroenterologist and liver specialist, antioxidants such as vitamin E might halt wasting in humans if these supplements were delivered in very high amounts—or even better, if they were targeted to the liver.
"One solution will be to find a liver-specific antioxidant," he said. "With the technology we have today, this is very feasible. We believe this will provide an exciting avenue for intervention."
Dr. Chojkier also noted that there are already medications on the market, albeit for different conditions, which work by preventing phosphorylation, or the addition of a phosphorous molecule.
These drugs could conceivably work in the liver to restore the normal production of albumin and treat wasting. Drs. Buck and Chojkier said they hope to test already available compounds with the goal of finding one that is safe and effective for wasting.
Catabolic wasting, or cachexia (ka-kek’-sia), breaks down body tissue, regardless of how much nutrition the patient absorbs.
"It’s like a car that burns too much fuel," said Dr. Chojkier.
The condition affects about half of all patients with cancer and AIDS and also affects patients with bacterial and parasitic diseases, rheumatoid arthritis, and chronic diseases of the bowel, liver, lungs and heart. Infusions of albumin are occasionally used to treat the condition, but the treatment is expensive, complicated, and only suitable for certain patients.
Collaborating on the study with Drs. Buck and Chojkier were Lian Zhang and Nicholas A. Halasz of VA and UCSD, and Tony Hunter of the Salk Institute for Biological Studies.
Funding for the study was provided by the Department of Veterans Affairs, the United States Public Health Service and the American Liver Foundation.