Abstract
Neutrophil extracellular traps (NETs) are cytotoxic DNA-protein complexes that play positive and negative roles in combating infection, inflammation, organ damage, autoimmunity, sepsis and cancer. However, NETosis regulatory effects of most of the clinically used drugs are not clearly established. Several recent studies highlight the relevance of NETs in promoting both cancer cell death and metastasis. Here, we screened the NETosis regulatory ability of 126 compounds belonging to 39 classes of drugs commonly used for treating cancer, blood cell disorders and other diseases. Our studies show that anthracyclines (e.g., epirubicin, daunorubicin, doxorubicin, and idarubicin) consistently suppress both NADPH oxidase-dependent and -independent types of NETosis in human neutrophils, ex vivo. The intercalating property of anthracycline may be enough to alter the transcription initiation and lead NETosis inhibition. Notably, the inhibitory doses of anthracyclines neither suppress the production of reactive oxygen species that are necessary for antimicrobial functions nor induce apoptotic cell death in neutrophils. Therefore, anthracyclines are a major class of drug that suppresses NETosis. The dexrazoxane, a cardioprotective agent, used for limiting the side effects of anthracyclines, neither affect NETosis nor alter the ability of anthracyclines to suppress NETosis. Hence, at correct doses, anthracyclines together with dexrazoxane could be considered as a therapeutic candidate drug for suppressing unwanted NETosis in NET-related diseases.
Highlights
Neutrophils are the most abundant leukocyte in circulating blood and act as a first line of immune defense [1]
We show that the anthracycline class of drugs, such as epirubicin, daunorubicin, doxorubicin, and idarubicin are able to drastically suppress NETosis through both the Nox-dependent and -independent pathways
Of interest are the effects of the anthracyclines, as four of the five drugs in this class, epirubicin, daunorubicin, doxorubicin, and idarubicin, greatly suppressed NETosis in the presence of each of the four agonists PMA, LPS, A23187 and ionomycin
Summary
Neutrophils are the most abundant leukocyte in circulating blood and act as a first line of immune defense [1]. As part of the innate immunity, neutrophils protect the host through phagocytosis, release of cytotoxic molecules, and release of neutrophil extracellular traps (NETs). NET formation (NETosis), was discovered by Takei et al [2]. NETosis can be induced when neutrophils are in a hypoxic cancer microenvironment [14]. When NETosis is induced without regulation, NETs can damage surrounding cells, tissue and organs. These NETs may protect tumor cells from the host’s immune system [15]. NETs are involved in thrombosis through acting as a scaffold for platelet and red blood cell interactions [15], and can be Cancers 2019, 11, 1328; doi:10.3390/cancers11091328 www.mdpi.com/journal/cancers
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