Cancer drugs offer new hope for treating sepsis

Research led by the IGC shows how these drugs limit inflammation and positions them as potential treatments for sepsis.

The study, published in eLife, shows that this class of drugs used in cancer treatment limits the immune system’s unchecked production of inflammatory mediators. The discovery positions these drugs as potential treatments for inflammatory diseases, such as sepsis, that cause as many or more deaths than oncological diseases. The data also reveal previously unknown mechanisms that likely contribute to the effectiveness of these drugs in chemotherapy.

The body’s extreme response to infection, a condition called sepsis, kills 11 million people every year. Because in order to survive a serious infection, it is not enough to get rid of the infectious agent, which is currently being done relatively effectively; It is also necessary to limit the damage that these and the immune response cause to the organs. The Innate Immunity and Inflammation research group at the IGC focuses on this second aspect, which is not yet part of the therapeutic intervention in sepsis.

The solution could be a class of drugs commonly used to treat cancer: anthracyclines. In the past, the team has shown that these drugs prevent organ failure in mice with sepsis without affecting exposure to the infectious agent. This discovery inspired a clinical study in Germany investigating whether the use of anthracyclines improves the course of sepsis and reduces the risk of death in patients. But to take full advantage of these drugs, we need to understand how they confer tolerance to infection.

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To investigate this, the researchers tested various anthracyclines in cells of the immune system of mice. The results were surprising: these cancer drugs limited the pro-inflammatory mediators produced by the cells when given in low doses. This effect persisted when the researchers treated mice with sepsis with these drugs.

The next challenge was to understand how these drugs control inflammation.

We discovered that anthracyclines control relevant inflammatory genes in cells of the immune system.”

Ana Neves-Costa, researcher at IGC and co-author of the study

By forming a complex with the cell’s DNA, these drugs avoid binding to factors that drive the expression of these genes. As a result, the cells produce fewer inflammatory molecules. “This new mechanism is particularly important because it lacks the side effects caused by the administration of high doses of these compounds in chemotherapy,” adds the researcher.

“With this work, we have found a possible new solution to more effectively treat diseases caused by excessive inflammation, such as sepsis and rheumatoid arthritis,” explains Luís Moita, MD and principal investigator at the IGC, who is leading the study. “Given that these drugs are already approved for use in clinics, it will be much easier to reuse them for new treatments than to start from scratch,” he adds. It is also likely that the regulation of gene expression described in this study and the limitation of inflammation, which have not been recognized previously, contribute to the effectiveness of anthracyclines in cancer treatment.

This study was developed by the Instituto Gulbenkian de Ciência in collaboration with several national and international institutions, notably the Instituto de Medicina Molecular (IMM) in Portugal, the Institute for Structural Biology and the European Molecular Biology Laboratory (EMBL) in Germany and the Leiden University Medical Center in the Netherlands. Funding was provided by the European Commission Horizon 2020 and Fundação para a Ciência e Tecnologia (FCT).

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