New cancer fighter may help ICU patients beat infections

August 27, 2007

HSP 90 inhibitors, which are finding favor in fighting cancer, may also help battle overwhelming infection in intensive care patients, researchers say.

Studies in an animal model of sepsis, a major cause of ICU patient death, indicate HSP 90 inhibitors help degrade proteins perpetuating inflammation, says Dr. John D. Catravas, director of the Medical College of Georgia Vascular Biology Center.

Results include restored lung function, reduced blood vessel leakage, which can lead to dangerous swelling in the lungs, and fewer byproducts of inflammation such as white blood cells, MCG researchers report in the American Journal of Respiratory and Critical Care Medicine, a journal of the American Thoracic Society.

They already have begun looking at the impact of HSP 90 inhibitors on the function of other organs, such as the liver and kidneys, also typically impacted by sepsis.

"We would die without an inflammatory response, but unreined inflammation is bad," says Dr. Catravas. That's just what happens with overwhelming infection; inflammation, which helps the body eliminate invaders, essentially keeps working after invaders are gone and the new target is the body.

"These are proteins that initially are useful in combating an invading bacteria but then, in some of us that develop sepsis for reasons that are poorly understood, the inflammatory response is amplified and stays much longer than it should," says Dr. Catravas, the paper's corresponding author.

Heat shock proteins carry proteins where they are needed and fold them up nicely so they do the correct job. Dr. Catravas compares their two-protein configuration to a lobster with its claws closed while tending to "client" proteins.

"The hypothesis we worked on is that these HSP 90 inhibitors take the heat shock protein and move it into a different conformation," says Dr. Catravas. The published research indicates they were correct and that inhibitors, fortunately, readily target proteins that no longer have a useful function.

"The HSP 90 inhibitor binds to a little pocket in the dimer, the two identical proteins that make up HSP 90 complex, and forces the two claws open," he says. "As soon as they open, as soon as the three-dimensional conformation of the HSP dimer and the client protein change, other proteins start attaching to the complex." The client protein then becomes susceptible to degradation. It was their earlier finding that inducible nitric oxide synthase, a major mediator of sepsis, is a client protein of HSP 90 that led to the inhibitor study.

For the study, researchers used what would be considered lethal doses of endotoxin to create a worse-case infection and pretreated animals with smaller doses of HSP 90 than those currently under study for a wide range of cancers.

They have begun looking at more clinically relevant infection levels and identifying the best time after the insult to give the lowest dose. However, Dr. Catravas has not ruled out HSP 90 inhibitors' potential to preventively treat patients at risk because patients seem to tolerate it well in the cancer clinical trials.

He hopes to move ahead soon with clinical trials of HSP 90 inhibitors, used in conjunction with antibiotics, in intensive care patients.

These manmade HSP 90 inhibitors work by attaching where the protein pair's energy source, called ATP, should be. The body appears to have an endogenous version, ADP, which has one less phosphate than ATP and binds at the same site, also opening the protein claws and sending the client protein toward degradation.
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The research was funded by the National Institutes of Health.

Medical College of Georgia at Augusta University

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