Matrix metalloproteinase inhibitor properties of tetracyclines: Therapeutic potential in cardiovascular diseases

Castro, Michele M.; Kandasamy, Arulmozhi D.; Youssef, Nermeen; Schulz, Richard

doi:10.1016/j.phrs.2011.05.005

Cited by 82 publications

(69 citation statements)

References 156 publications

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“…The association constant of tetracyclines to MMPs is not high (Kd = 70 µM), but as result of accumulation in the ECM, they can inhibit proteases. The higher the tetracycline concentration in the matrix, the more inhibition can be achieved (32).…”

Section: Discussionmentioning

confidence: 99%

Minocycline is More Potent Than Tetracycline and Doxycycline in Inhibiting MMP-9 in Vitro

Modheji

Olapour

Khodayar

et al. 2016

Jundishapur J Nat Pharm Prod

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Background: Tetracyclines are antimicrobial agents that possess anti-inflammatory and matrix metalloproteinase (MMP) inhibitory effects. Tetracycline, doxycycline, and minocycline have shown different potencies in inhibiting various MMPs. MMPs are a conserved family of zinc-dependent endopeptidases, which are involved in various physiologic and pathologic conditions. MMP-9 is among the most important proteases involved in the development of cardiovascular disease, cancer, and inflammatory disease Objectives: Considering the central role of MMP-9 in the above-mentioned diseases and the variable inhibitory potentials of routine tetracyclines, including tetracycline, doxycycline, and minocycline, this study measured the inhibitory effect of these routine tetracycline agents on MMP-9 activity obtained from U-937 cell cultures using the zymography method. Materials and Methods: An MMP-9-rich culture medium of U-937 cells was used as the source of the enzyme. Serial dilutions of 5, 20,

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Section: Discussionmentioning

confidence: 99%

Minocycline is More Potent Than Tetracycline and Doxycycline in Inhibiting MMP-9 in Vitro

Modheji

Olapour

Khodayar

et al. 2016

Jundishapur J Nat Pharm Prod

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“…Like most other studies of doxycycline, and many tetracyclines, the mechanism of inhibition was thought to be due its activity as an MMP inhibitor (29,31). All tetracyclines feature an enol backbone that has divalent cation binding activity responsible for the reported MMP inhibition found in several members of this class (30). However, recent studies of MMP 9 inhibition by doxycycline in vitro show the effective dose range to be 50-100 mM (31).…”

Section: Discussionmentioning

confidence: 99%

“…The family of tetracyclines is reported to inhibit MMP activity through chelation of the zinc ion at the active site of the enzyme (30). The ability of doxycycline to attenuate fibrosis was thought to be due to inhibition of MMP activity (29,31).…”

Section: Inflammation and Macrophage Tgf-b1 Signaling Are Not Affectementioning

confidence: 99%

Inhibition of Epithelial-to-Mesenchymal Transition and Pulmonary Fibrosis by Methacycline

Tan

Brumwell

et al. 2014

Am J Respir Cell Mol Biol

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A high-throughput small-molecule screen was conducted to identify inhibitors of epithelial-mesenchymal transition (EMT) that could be used as tool compounds to test the importance of EMT signaling in vivo during fibrogenesis. Transforming growth factor (TGF)-b1-induced fibronectin expression and E-cadherin repression in A549 cells were used as 48-hour endpoints in a cell-based imaging screen. Compounds that directly blocked Smad2/3 phosphorylation were excluded. From 2,100 bioactive compounds, methacycline was identified as an inhibitor of A549 EMT with the half maximal inhibitory concentration (IC50) of roughly 5 mM. In vitro, methacycline inhibited TGF-b1-induced a-smooth muscle actin, Snail1, and collagen I of primary alveolar epithelial cells . Methacycline inhibited TGF-b1-induced non-Smad pathways, including c-Jun N-terminal kinase, p38, and Akt activation, but not Smad or b-catenin transcriptional activity. Methacycline had no effect on baseline c-Jun N-terminal kinase, p38, or Akt activities or lung fibroblast responses to TGF-b1. In vivo, 100 mg/kg intraperitoneal methacycline delivered daily beginning 10 days after intratracheal bleomycin improved survival at Day 17 (P , 0.01).Bleomycin-induced canonical EMT markers, Snail1, Twist1, collagen I, as well as fibronectin protein and mRNA, were attenuated by methacycline (Day 17). Methacycline did not attenuate inflammatory cell accumulation or alter TGF-b1-responsive genes in alveolar macrophages. These studies identify a novel inhibitor of EMT as a potent suppressor of fibrogenesis, further supporting the concept that EMT signaling is important to lung fibrosis. The findings also provide support for testing the impact of methacycline or doxycycline, an active analog, on progression of human pulmonary fibrosis.

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“…Doxycycline, a tetracycline antibiotic, is the only licensed drug that exhibits inhibition of MMP-1, MMP-2 and MMP-9 [38] which are implicated in LAM and, thus, prompted the choice of doxycycline for this trial. In addition, some suggestion for a benefit of doxycycline in LAM had come from a previous case report and observational studies [39][40][41].…”

mentioning

confidence: 99%

Treatment of lymphangioleiomyomatosis: building evidence in orphan diseases

Cottin¹

2014

European Respiratory Journal

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Matrix metalloproteinase inhibitor properties of tetracyclines: Therapeutic potential in cardiovascular diseases

Cited by 82 publications

References 156 publications

Minocycline is More Potent Than Tetracycline and Doxycycline in Inhibiting MMP-9 in Vitro

Minocycline is More Potent Than Tetracycline and Doxycycline in Inhibiting MMP-9 in Vitro

Inhibition of Epithelial-to-Mesenchymal Transition and Pulmonary Fibrosis by Methacycline

Treatment of lymphangioleiomyomatosis: building evidence in orphan diseases

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