NIH-funded study reveals topoisomerase 1 inhibitors suppress inflammation in mice.
Results from laboratory experiments and mouse studies suggest that small doses of drugs from a specific class of approved cancer medications called topoisomerase 1 (top1) inhibitors may protect against the overwhelming immune response to infection that sometimes leads to sepsis, a bacterial condition that kills as many as 500,000 people in the United States each year. The research, supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), appears in the April 28, 2016 issue of Science.
Viral and bacterial infections can cause the human body to produce a massive inflammatory response leading to sepsis, which often results in tissue damage, organ failure and in some cases, death. Anyone with an infection can develop sepsis; however, people with weakened immune systems; babies and young children; the elderly; individuals with chronic illnesses, such as diabetes; and people with severe burns and wounds are at greatest risk. Viruses such as Ebola and novel influenza strains also can trigger similar and sometimes deadly immune responses. Treatments to dampen this over-exuberant inflammatory response without weakening the body's ability to fight infection are urgently needed, according to the authors.
Led by scientists from the Icahn School of Medicine at Mount Sinai in New York, the research team conducted laboratory experiments that revealed that during infection the enzyme topoisomerase 1 activates genes that produce a strong inflammatory response. This suggested that impeding the enzyme could be an effective way to suppress an overwhelming inflammatory response while still allowing the normal immune response to work.
The scientists found that 70 to 90 percent of mice treated with one to three doses of the top1 inhibitor cancer drug camptothecin were rescued from a lethal inflammatory response caused by infection with the bacteria Staphylococcus aureus (S. aureus), co-infection with influenza and S. aureus, or liver failure. A laboratory experiment also found that inhibiting topoisomerase 1 in human cells suppressed inflammatory genes induced by Ebola virus. Together, the data suggest that anti-top1 cancer drugs potentially could help control acute infections that induce an exacerbated inflammatory response and deserve further exploration, according to the researchers.
Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. Alex Rialdi, Laura Campisi, Nan Zhao, Arvin Cesar Lagda, Colette Pietzsch, Jessica Sook Yuin Ho, Luis Martinez-Gil, Romain Fenouil, Xiaoting Chen, Megan Edwards, Giorgi Metreveli, Stefan Jordan, Zuleyma Peralta, Cesar Munoz-Fontela, Nicole Bouvier, Miriam Merad, Jian Jin, Matthew Weirauch, Sven Heinz, Chris Benner, Harm van Bakel, Chris Basler, Adolfo García-Sastre, Alexander Bukreyev, Ivan Marazzi. Science. DOI:10.1126/science.aad7993. Published online April 28, 2016.