A Novel Peptidylarginine Deiminase 4 (PAD4) Inhibitor BMS-P5 Blocks Formation of Neutrophil Extracellular Traps and Delays Progression of Multiple Myeloma.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
Cell Proliferation
Enzyme Inhibitors
/ pharmacology
Extracellular Traps
/ drug effects
Female
Humans
Male
Mice
Mice, Inbred C57BL
Multiple Myeloma
/ drug therapy
Protein-Arginine Deiminase Type 4
/ antagonists & inhibitors
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
27
10
2019
revised:
25
03
2020
accepted:
01
05
2020
pubmed:
7
5
2020
medline:
3
6
2021
entrez:
7
5
2020
Statut:
ppublish
Résumé
Multiple myeloma is a plasma cell malignancy, which grows in the bone marrow (BM). The major population of cells in the BM is represented by neutrophils and they can form neutrophil extracellular traps (NET). Here, we investigated whether multiple myeloma cells induce NET formation and whether targeting this process would delay multiple myeloma progression. We demonstrated that murine and human multiple myeloma cells stimulate citrullination of histone H3 and NET formation by neutrophils and that this process is abrogated by pharmacological targeting of peptidylarginine deiminase 4 (PAD4) with a novel-specific small molecule inhibitor BMS-P5. Administration of BMS-P5 to multiple myeloma-bearing mice delays appearance of symptoms and disease progression. Taken together, our data demonstrate that targeting PAD4 may be beneficial for treatment of multiple myeloma.
Identifiants
pubmed: 32371579
pii: 1535-7163.MCT-19-1020
doi: 10.1158/1535-7163.MCT-19-1020
pmc: PMC7335350
mid: NIHMS1592757
doi:
Substances chimiques
Antineoplastic Agents
0
Enzyme Inhibitors
0
Protein-Arginine Deiminase Type 4
EC 3.5.3.15
peptidylarginine deiminase 4, mouse
EC 3.5.3.15
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1530-1538Subventions
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA196788
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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