Table 2.
List of studies targeting NETs in various diseases.
| Studies | Therapeutic Agents | Targets | Mechanism of Action | Major Findings | Disease/Model |
|---|---|---|---|---|---|
| Yang et al. [94] | DNase 1 | DNA backbone of NETs | Digestion of NETs | Diminished colorectal cancer liver metastasis. | CRC (in vivo) |
| Xia et al. [101] | Adeno-associated virus (AAV)-mediated gene transfer of DNase I | DNA backbone of NETs | Digestion of NETs | Reduced liver metastasis in a mouse model of CRC liver metastasis. | CRC (in vivo) |
| Rayes et al. [102] | DNase | DNA backbone of NETs | Digestion of NETs | Inhibited CRC cell adhesion and migration in vitro. Reduced liver metastasis of CRC cells. | CRC (in vivo and in vitro) |
| CEACAM1 blocking antibody | NET-associated CEACAM1 | Blocking of CEACAM1 on NETs | |||
| Shang et al. [82] | DNase | DNA backbone of NETs | Degradation of NETs | Reduced KRAS mutant exosome-induced CRC cells adhesion. | CRC (in vitro) |
| Shah et al. [104] | DNase | DNA backbone of NETs | Degradation of NETs | Reduced viscoelasticity of sputum and improved pulmonary function. | Cystic fibrosis (clinical trials) |
| Li et al. [47] | DNase | DNA backbone of NETs | Degradation of NETs | Lessened cytokine levels, attenuated thrombus formation and activation of platelet. | DSS-induced colitis (in vivo) |
| Park et al. [65] | DNase | DNA backbone of NETs | Degradation of NETs | Inhibited NET-induced invasion and migration of breast cancer cells in vitro. Reduced breast cancer cells metastasis to lung. | Breast cancer (in vitro and in vivo) |
| Xiao et al. [126] | AZD7986 (inhibitor of Cathepsin C) | Cathepsin C | Inhibit CTSC-PR3-IL-1β axis mediated reactive oxygen species production | Reduced lung metastasis of breast cancer in a mouse model. | Breast cancer (in vivo) |
| Wen et al. [106] | DNase | Extracellular DNA (exDNA) | Degradation of exDNA | Suppressed metastasis of pancreatic cancer cells in an orthotopic xenograft model. | Pancreatic cancer (in vivo) |
| Sollberger et al. [118] | Gasdermin D Inhibitor (LDC7559) | Pore-forming protein Gasdermin D (GSDMD) | LDC7559 binds to GSDMD and prevents pore formation in granule membrane | Decreased phorbol 12-myristate 13-acetate (PMA)-induced NET formation. | In vitro |
| Khan et al. [112] | Actinomycin D and Topoisomerase I inhibitor | Promoter region of DNA | Inhibit protein transcription initiation | Blocking of transcription suppresses NETosis without affecting ROS generation. | In vitro |
| Lood et al. [113] | MitoTEMPO | ROS | MitoTEMPO scavenge mitochondrial superoxide | Mitochondrial ROS inhibition reduced NET formation and systemic lupus erythematosus (SLE) disease severity. | SLE (in vivo and in vitro) |
| Apocynin | ROS | Block superoxide production | Reduced PMA-induced NET formation. | ||
| VAS2870 | ROS | Inhibit NADPH-oxidase (NOX) | Reduced PMA-induced NET formation. | ||
| Van Avondt et al. [114] | Diphenyleneiodonium (DPI) | NADPH-oxidase | Inhibit ROS generation | Reduced PMA-induced NET formation. | In vitro |
| Knight et al. [115] | Cl-amidine and BB-Cl-amidine | PAD4 | Inhibit PAD4 | PAD inhibition diminished NET formation and showed protection against lupus-related damage to vasculature, kidney in murine lupus model. | SLE (in vivo) |
| Maronek et al. [39] | Cl-amidine and Streptonigrin | PAD4 | Inhibit PAD4 | Reduced plasma level of ecDNA but could not lessened total UC condition in mice. | DSS-induced UC (in vivo) |
| Dinallo et al. [46] | Infliximab (anti-TNF-α antibody) |
TNF-α | Block TNF-α | Reduced PAD4 expression and TNF-α-driven NETosis. | UC (in vivo) |
| Zheng et al. [119] | PF-1355 | MPO | Inhibition of MPO | Decreased neutrophil recruitment and NETosis. | In vitro |
| Parker et al. [120] | ABAH (4-aminobenzoic acid hydrazide) |
MPO | Inhibition of MPO | Reduced PMA-induced NET formation. | In vitro |
| TX1 (3-isobutyl-2-thioxo-7H-purine-6-one) | |||||
| Smith et al. [127] | Chloroquine | Reduced LPS-induced NET formation. | In vitro | ||
| Fuchs et al. [128] | Heparin | Histones | Remove histones from NETs and destabilize NETs | Reduced NET formation. | In vitro |
| Manda-Handzlik et al. [129] | Apocynin and DPI | NADPH-oxidase | Inhibit NADPH-oxidase activity | Reduced S-nitroso-N-acetyl-D,L-penicillamine (SNAP)-induced NET formation. |
In vitro |
| N-acetylcysteine (NAC) |
ROS scavenger | Interfere with the levels of hydrogen peroxide and hydroxyl radical | Inhibited NO-dependent NETosis | ||
| Li et al. [117] | SMT | Inducible NO synthase (iNOS) | Block NO synthesis | Inhibited NO-mediated NET formation | In vitro |
| L-NAME | Endothelial NO synthase (eNOS) | ||||
| L-NMMA | Total NOS | ||||
| Wang et al. [34] | Metformin (antidiabetic) | Inhibit mitochondrial respiratory chain complex I and NADPH-oxidase activity, thus decrease ROS production | Reduced PMA-induced NET formation | In vitro | |
| Menegazzo et al. [124] | Metformin (antidiabetic) | Inhibit membrane translocation of PKC-βII and activation of NADPH-oxidase | Reduced NET components elastase, proteinase-3, histones, and double strand DNA in the plasma of pre-diabetes. | Pre-diabetes (in vivo and in vitro) | |
| Zhang et al. [125] | Hydroxychloroquine (autophagy inhibitor) | Inhibit PAD4 and Rac2 expressions by blocking TLR9 | Reduced hepatic ischemia/reperfusion (I/R) injury by inhibiting NET formation. | Hepatic I/R injury (in vivo and in vitro) | |
| Phase II clinical trial (NCT02462265, https://clinicaltrials.gov) Accessed on 30 June 2021 | Oshadi D (DNase) and Oshadi R (RNase) | DNA and RNA | Showed antitumor activity and a good safety profile in leukemia patients. | Acute myeloid leukemia or acute lymphoid leukemia |