Research conducted by the IGC shows that these drugs can control inflammation, making them potential treatments for sepsis.
Sepsis, the body’s extreme reaction to an infection, claims 11 million lives annually. Simply eliminating the infectious agent is not enough to survive a severe infection, it is also crucial to mitigate the harm caused by both the infection and the immune response to the organs. The Innate Immunity and Inflammation research group at the IGC focuses on this second aspect, which is still not a part of the therapeutic intervention on sepsis.
A potential solution could come from a class of drugs commonly used in cancer treatment: anthracyclines. The research team previously showed that these drugs can prevent organ failure in mice with sepsis without impacting the infection itself. This sparked a clinical trial in Germany to determine if the use of anthracyclines can improve sepsis outcomes and lower the risk of death in patients. However, to fully utilize these drugs, it is necessary to comprehend how they provide tolerance to infection.
To explore this, researchers tested different anthracyclines in the immune system cells of mice. The results were surprising: these anticancer drugs limited the levels of pro-inflammatory mediators produced by the cells when administered in low doses. This effect was maintained when 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 the immune system cells”, explains Ana Neves-Costa, a researcher at the IGC and co-author of the study. By forming a complex with the cell’s DNA, these drugs avoid the binding of factors that drive the expression of these genes. As a result, cells produce less inflammatory molecules. “This new mechanism is particularly important because it lacks the side effects caused by administering high doses of these compounds in chemotherapy”, the researcher adds.
“With this work we found a possible new solution to treat diseases caused by exaggerated inflammation, such as sepsis and rheumatoid arthritis, more effectively”, explains Luís Moita, a doctor by training and principal investigator at the IGC leading the study. “Given that these drugs are already approved for use in the clinics, repurposing these for new treatments will be much easier than starting from scratch”, he adds. It is also likely that the regulation of gene expression and the limitation of inflammation described in this study, which were previously unrecognized, contribute to the effectiveness of anthracyclines in cancer treatment.
Reference: “DNA damage independent inhibition of NF-κB transcription by anthracyclines” by Angelo Ferreira Chora, Dora Pedroso, Eleni Kyriakou, Nadja Pejanovic, Henrique Colaço, Raffaella Gozzelino, André Barros, Katharina Willmann, Tiago Velho, Catarina F Moita, Isa Santos, Pedro Pereira, Silvia Carvalho, Filipa Batalha Martins, João A Ferreira, Sérgio Fernandes de Almeida, Vladimir Benes, Josef Anrather, Sebastian Weis, Miguel P Soares, Arie Geerlof, Jacques Neefjes, Michael Sattler, Ana C Messias, Ana Neves-Costa and Luis Ferreira Moita, 7 December 2022, eLife.
This study was developed by the Instituto Gulbenkian de Ciência in collaboration with several national and international institutions, in particular the Instituto de Medicina Molecular (IMM) in Portugal, the Institute of Structural Biology and the European Molecular Biology Laboratory (EMBL) in Germany, and the Leiden University Medical Center in the Netherlands.
The study was funded by the European Commission Horizon 2020 and Fundação para a Ciência e Tecnologia (FCT).