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.

CD147 as a Target for COVID-19 Treatment: Suggested Effects of Azithromycin and Stem Cell Engagement

“…Interestingly, doxycycline, an antibiotic analogue of tetracycline, reduced CD147 levels in a gallbladder carcinoma cell line [19] and gingival crevicular fluid (soluble form) in patients with chronic periodontitis [20]. In addition, monocytes and peripheral blood mononuclear cells treated with azithromycin expressed less MMP-9 [21,22], as well as airways of lung transplant patients did upon treatment with azithromycin [23]. Furthermore, MMP-3 and MMP-1 expression was reduced in respiratory epithelial cells in vitro following azithromycin treatment [24].…”

“…Furthermore, MMP-3 and MMP-1 expression was reduced in respiratory epithelial cells in vitro following azithromycin treatment [24]. In fact, several studies have demonstrated that azithromycin decreases MMP expression and action [21][22][23][24]. Despite CD147 and MMPs are closely related molecules, further studies are necessary to evaluate whether azithromycin directly changes expression levels of the CD147 receptor.…”

Post-Translational Modification-Dependent Activity of Matrix Metalloproteinases

“…The presence of these O -linked glycans increases the domain flexibility of MMP9, allowing the protease to adopt multiple enzyme conformations and facilitating individual movements of the catalytic and the hemopexin domain. This influences the recognition, binding, and processing of substrates, cell receptors, and endogenous inhibitors [62,63]. A study by den Steen et al described that the OG domain is indispensable for correct orientation of the hemopexin domain for MMP9 internalization and degradation by LRP-1 and LRP-2, as well as inhibition by endogenous TIMP1 [60].…”

Tetracycline Analogs Inhibit Osteoclast Differentiation by Suppressing MMP-9-Mediated Histone H3 Cleavage

“…We recently demonstrated that the matrix metalloproteinase MMP-9 is the key protease involved in histone H3 tail cleavage during osteoclast differentiation [6]. Since tetracycline analogs are known to act as MMP-9 inhibitors [19,20], studying their possible effects on MMP-9-mediated H3 tail proteolysis was a logical extension of our study. To this end, we first attempted to identify the optimal inhibitor(s) of MMP-9 from the four tetracyclines currently in use.…”