A well-known anticancer drug also binds a protein in the human body that triggers sepsis, researchers at Emory University School of Medicine have revealed.
In mice, the drug paclitaxel can bring on symptoms resembling sepsis, a life-threatening inflammation caused by systemic infection. Luckily for thousands of cancer patients, paclitaxel doesn't act similarly in humans.
Solving this puzzle could help scientists better understand how paclitaxel works and develop new drugs to quench sepsis, says Shanta Zimmer, MD, assistant professor of medicine (infectious diseases), Emory University School of Medicine.
Zimmer teamed up with James P. Snyder, PhD, director of biostructural research at Emory and an expert on paclitaxel and its chemical relatives, to probe how the drug binds to a protein called MD-2.
"Paclitaxel was not crafted by nature to bind to MD-2," Snyder says. "Many other molecules more easily prepared in the laboratory should behave similarly. Of particular interest are those that block rather than stimulate inflammation. We intend to find them."
The team's results are published online and in the Oct. 10 issue of Journal of Biological Chemistry. Zimmer, whose laboratory is located at Atlanta Veterans Affairs Medical Center, is first author and Snyder is the senior author.
"We were able to demonstrate that paclitaxel doesn't induce an inflammatory response through human MD-2, but binding does occur," says Zimmer. "The difference seems to be in a particular loop area of MD-2, which changes shape when MD-2 binds."
MD2 is an accessory molecule to the most important receptor in sepsis, which can be found on the surface of white blood cells and senses the presence of bacterial products called endotoxins.
In both mice and humans, MD2 cooperates with several other proteins to drive inflammation when it encounters endotoxin. However in humans, the loop area of MD2 doesn't appear to form a "bridge" with the other proteins when paclitaxel binds, says Zimmer.
The team combined laboratory tests of how well paclitaxel sticks to purified MD2 protein from mice and humans with a computer simulation of the drug binding, taking advantage of existing structural information about MD2 gained by X-ray crystallography.
"If we can predict these kinds of interactions, it could guide the search for new medications that might interfere with MD2," she says.
Paclitaxel is a naturally-occurring anticancer compound found in the bark of the Pacific yew tree by National Cancer Institute scientists in the 1960s. It interferes with cell division by locking microtubules, the building blocks of the cell's internal skeleton, into place.
Cardiologists have also incorporated paclitaxel into stents, with the purpose of preventing the growth of scar tissue after stents are placed in coronary arteries.
The origin of paclitaxel's inflammatory effects in mice were only discovered in the last decade by scientists in Japan.
"There have been hints that some of paclitaxel's effects on blood vessels in people come by this mechanism, rather than its effects on cell division," notes Zimmer.
Probing those effects and whether chemical relatives of paclitaxel act similarly are next on her list, she says.
The study was funded by the National Institutes of Health.
Reference: S.M. Zimmer et al, Paclitaxel binding to human and murine MD-2. Journal of Biological Chemistry, Vol. 283, Issue 41, 27916-27926, Oct. 10, 2008.