Anthracyclines Suppress Both NADPH Oxidase- Dependent and -Independent NETosis in Human Neutrophils

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.

A Bittersweet Response to Infection in Diabetes; Targeting Neutrophils to Modify Inflammation and Improve Host Immunity

“…As a last resort in the anti-microbial defence strategy neutrophils undergo a programmed cell death known as NETosis, in order to (177)(178)(179)(180). Chromatin decondensation, a key part of NETosis, is mediated by protein arginine deiminase 4 (PAD-4), which citrullinates DNA, as well as myeloperoxidase and neutrophil elastase (181)(182)(183).…”

“…As a last resort in the anti-microbial defence strategy neutrophils undergo a programmed cell death known as NETosis, in order to capture extracellular bacteria. The release of NETs, which are extruded DNA networks decorated with antimicrobial proteins and histones, can occur via ROS dependant or ROS independent pathways ( 177 – 180 ). Chromatin decondensation, a key part of NETosis, is mediated by protein arginine deiminase 4 (PAD-4), which citrullinates DNA, as well as myeloperoxidase and neutrophil elastase ( 181 – 183 ).…”

Neutrophils: Many Ways to Die

“…Originally, it was reported that the presence of NADPH oxidase and myeloperoxidase (MPO) was necessary for the correct formation of NETs; until recently, all the activators capable of inducing NETs formation were known to require in some manner the presence of ROS ( 96 ). However, this has been a controversial theme in recent years due to the description of novel NETosis activation pathways that appear to be independent of NADPH oxidase ( 81 , 97 , 98 ).…”

Neutrophils in Tumorigenesis: Missing Targets for Successful Next Generation Cancer Therapies?

“…The molecules of the anthracycline class intercalate between base pairs of DNA and RNA strands during DNA or RNA synthesis [90] and disrupt the activity of topoisomerase 2, which is essential for DNA replication [91]. It has been reported that anthracyclines can suppress NETosis through their intercalating activity, resulting in the alteration of the de-condensation process and thus in the abrogation of NET formation [92].…”