Inflammation may help you fight off invading microbes, but it can also kill you, leading to insufficient blood flow and even organ failure. A new study shows that some cancer drugs may be able to quell the excessive inflammation that occurs in conditions such as sepsis, which is responsible for more than 250,000 deaths in the United States each year.
Inflammation is a normal immune response to a pathogen threat, involving the production of various chemical signals and the activation of immune cells like neutrophils. Yet its effects can be deadly on a massive scale. Researchers suspect, for example, that the 1918–1919 flu pandemic, which killed as many as 40 million, was so lethal because it sent inflammation spiraling out of control. Over-the-top inflammation is also a hallmark of sepsis, in which the body overreacts to an infection. There are few options for treating people with sepsis, which can cause their organs to stop working and can be fatal within hours.
Molecular biologist Ivan Marazzi of the Ichan School of Medicine at Mount Sinai in New York City and colleagues set out to explore how various cells control the activity of genes that promote inflammation. They exposed human and mouse cells to one of two viruses, activating the cells’ immune genes. The team then tested several different compounds that affect how DNA is packaged in cells—the idea being that the compounds might alter the activity of these genes. One of the compounds that curbed gene activity, camptothecin, is a cancer treatment. Of the tested compounds, Marazzi says. “it probably would have been the last” he would have expected to work.
Camptothecin kills cancer cells by blocking the enzyme topoisomerase I, which removes kinks from DNA so that it can be duplicated or read to produce proteins. The team’s findings suggest that topoisomerase I also helps orchestrate the immune system’s response to pathogen attacks.
To determine whether blocking topoisomerase I could thwart out-of-control inflammation, the researchers injected mice with a bacterial poison that triggers septic shock, a severe form of sepsis, and then dosed some of the mice with camptothecin. All of the untreated mice died within about 40 hours, whereas 90% of the mice that received camptothecin survived, the researchers report online today in Science. The drug also allowed 70% of mice to live through an infection with the bacterium Staphylococcus aureus, which can cause sepsis in humans. Only 11% of untreated animals survived the infection. People who have the flu are particularly susceptible to bacterial infections that can lead to sepsis. Marazzi and colleagues found that captothecin protected mice suffering from these dual infections, saving 94% of them, whereas all of the untreated mice perished.
The study “provides an extremely intriguing and promising strategy,” says immunopathologist Peter Ward of the University of Michigan, Ann Arbor, who wasn’t connected to the research. But he wants to see further animal studies to confirm that blocking topoisomerase is effective against other types of bacteria that more commonly cause sepsis in people.
The findings are encouraging, says molecular biologist Murat Kaynar of the University of Pittsburgh School of Medicine in Pennsylvania. However, he cautions that many potential sepsis treatments that were promising in animal studies haven’t panned out in human studies. “We’ve had a lot of failed trials,” he says.
Although topoisomerase I is not a specialized immune system enzyme, the researchers found that it has a big impact on some genes that control inflammation, says molecular immunologist Stephen Smale of the University of California, Los Angeles. Thus “the study by Marazzi and colleagues shows the value of broadening the search for inhibitors of inflammatory responses,” he says.
Camptothecin is one of several topoisomerase I–inhibiting cancer drugs that have received approval from the Food and Drug Administration. Marazzi says that he and his colleagues are working with a pharmaceutical company to organize a clinical trial to test whether blocking topoisomerase I is beneficial during sepsis. Although such inhibitors can trigger problems such as bleeding and infections, patients with sepsis would only need a small number of doses, so these side effects would be less likely, Marazzi predicts. “We have a potential treatment for a deadly disease that kills millions of people worldwide.”