title: Differential inhibition of activity, activation and gene expression of MMP-9 in THP-1 cells by azithromycin and minocycline versus bortezomib: A comparative study.
abstract: Gelatinase B or matrix metalloproteinase-9 (MMP-9) (EC 3.4.24.35) is increased in inflammatory processes and cancer, and is associated with disease progression. In part, this is due to MMP-9-mediated degradation of extracellular matrix, facilitating influx of leukocytes into inflamed tissues and invasion or metastasis of cancer cells. MMP-9 is produced as proMMP-9 and its propeptide is subsequently removed by other proteases to generate proteolytically active MMP-9. The significance of MMP-9 in pathologies triggered the development of specific inhibitors of this protease. However, clinical trials with synthetic inhibitors of MMPs in the fight against cancer were disappointing. Reports on active compounds which inhibit MMP-9 should be carefully examined in this regard. In a considerable set of recent publications, two antibiotics (minocycline and azythromycin) and the proteasome inhibitor bortezomib, used in cancers, were reported to inhibit MMP-9 at different stages of its expression, activation or activity. The current study was undertaken to compare and to verify the impact of these compounds on MMP-9. With exception of minocycline at high concentrations (>100 μM), the compounds did not affect processing of proMMP-9 into MMP-9, nor did they affect direct MMP-9 gelatinolytic activity. In contrast, azithromycin specifically reduced MMP-9 mRNA and protein levels without affecting NF-κB in endotoxin-challenged monocytic THP-1 cells. Bortezomib, although being highly toxic, had no MMP-9-specific effects but significantly upregulated cyclooxygenase-2 (COX-2) activity and PGE2 levels. Overall, our study clarified that azithromycin decreased the levels of MMP-9 by reduction of gene and protein expression while minocycline inhibits proteolytic activity at high concentrations.
authors.affiliation: Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Jennifer
authors.identifier: http://orcid.org/0000-0002-7157-3370
authors.initials: J
authors.lastname: Vandooren
authors.affiliation: Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Knoops
authors.affiliation: Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: João L
authors.initials: JL
authors.lastname: Aldinucci Buzzo
authors.affiliation: Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Lise
authors.initials: L
authors.lastname: Boon
authors.affiliation: Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Martens
authors.affiliation: Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Ghislain
authors.initials: G
authors.lastname: Opdenakker
authors.affiliation: Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, KU Leuven, Leuven, Belgium.|Department of Evolutionary Immunology, Jagiellonian University, Krakow, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Kolaczkowska
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017963:Azithromycin / Q000494:pharmacology*; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004731:Endotoxins; D015870:Gene Expression / Q000187:drug effects; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D008911:Minocycline / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D004731:Endotoxins; D006573:Heterocyclic Compounds, 1-Ring; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; C429533:SB 3CT compound; D013450:Sulfones; D000069286:Bortezomib; D017963:Azithromycin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D008911:Minocycline; D015232:Dinoprostone