The gelatinase inhibitory activity of tetracyclines and chemically modified tetracycline analogues as measured by a novel microtiter assay for inhibitors

Paemen, Liesbet; Martens, Erik; Norga, Koenraad; Masure, Stefan; Roets, Eugène; Hoogmartens, Jos; Opdenakker, Ghislain

doi:10.1016/0006-2952(96)00168-2

Cited by 104 publications

(74 citation statements)

References 23 publications

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“…88 Based on this finding and the appreciation that MMPs are involved in MS, we tested minocycline in EAE and found it to reduce disease activity. 90 This efficacy of minocycline in decreasing EAE disease has been reported by three other groups.…”

Section: Figmentioning

confidence: 99%

“…In this regard, an early literature indicating that tetracycline antibiotics are inhibitors of MMP enzymatic activity 87,88 has led to the use of these and chemically modified tetracyclines without anti-microbial activity (CMTs) as MMP inhibitors. Indeed, the only compound approved for clinical use based on its ability to inhibit MMPs is a low-dose doxycycline formulation, Periostat (CollaGenex Pharmaceuticals, NY).…”

Section: Figmentioning

confidence: 99%

“…The proposed mechanism for CMT as MMP inhibitors resides in their ability to bind Zn 2ϩ and Ca 2ϩ , the latter being required to maintain proper enzyme conformation. 8,88,89 Besides disrupting MMP enzyme activity, CMTs have also been shown to downregulate expression of MMPs, 90 and to decrease the oxidative activation of pro-MMPs into active enzymes.…”

Section: Figmentioning

confidence: 99%

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Targeting MMPs in Acute and Chronic Neurological Conditions

2007

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Summary:The matrix metalloproteinases (MMPs) are important enzymes that regulate developmental processes, maintain normal physiology in adulthood and have reparative roles at specific stages after an insult to the nervous system. Conversely, the concordant presence and significant upregulation of several MMP members in virtually all neurological conditions result in pathology. Thus, the MMPs have diverse functions, capable of mediating repair and recovery on the one hand and being involved in producing injury on the other. Therefore, targeting MMPs in neurological conditions has become a complicated challenge. This article highlights the beneficial roles of MMPs in normal and reparative processes within the nervous system and discusses the detriments of MMPs encountered in pathology. We review the availability of MMP inhibitors for clinical use and propose that an important consideration for these inhibitors is timing and duration of their use. With acute injuries where a massive upregulation of several MMPs are observed in the early periods after the insult, early and short-term use of broad spectrum MMP inhibitors would seem logical. In chronic conditions where recurrent insults to the CNS are accompanied by prolonged upregulation of MMPs, thereby necessitating the chronic use of medications, the beneficial effects of MMPs in repair may be compromised by the long-term application of MMP inhibitors. In this review we have used spinal cord injury and multiple sclerosis as examples of acute and chronic neurological conditions, respectively, and we consider the use of MMP inhibitors in these states.

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Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Targeting MMPs in Acute and Chronic Neurological Conditions

2007

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“…We focus on the potential MS medication minocycline, a tetracycline antibiotic that inhibits MMP activity (21) and reduces the severity of animals immunized for EAE (22)(23)(24). From these animal studies, minocycline was tested and found to have promise in relapsing-remitting MS as suggested by early clinical trials (25)(26)(27)(28).…”

mentioning

confidence: 99%

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

Hahn

Kaushik

Mishra

et al. 2016

The Journal of Immunology

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Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a transmembrane glycoprotein that is upregulated on leukocytes in active lesions in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Administration of anti-EMMPRIN Abs reduces the severity of EAE. Minocycline is a tetracycline antibiotic with immune-modulatory properties that decreases the severity of EAE; it was recently found to attenuate the conversion from a first demyelinating event to clinically definite MS in a phase III trial. We investigated whether and how minocycline affects the expression of EMMPRIN on T cells in culture and in mice afflicted with EAE. EMMPRIN expression in cultures of mouse splenocytes or human PBMCs was elevated upon polyclonal T cell activation, and this was reduced by minocycline correspondent with decreased P-Akt levels. An established MS medication, IFN-β, also diminished EMMPRIN levels on human cells whereas this was not readily observed for fingolimod or monomethylfumarate. In EAE-afflicted mice, minocycline treatment significantly reduced EMMPRIN levels on splenic lymphocytes at the presymptomatic (day 7) phase, and prevented the development of disease. Day 7 spleen transcripts from minocycline-treated EAE mice had a significantly lower MMP-9/TIMP-1 ratio, and significantly lower MCT-1 and CD98 levels, factors associated with EMMPRIN function. Day 16 (peak clinical severity) CNS samples from EAE mice had prominent representation of inflammatory perivascular cuffs, inflammatory molecules and EMMPRIN, and these were abrogated by minocycline. Overall, minocycline attenuated the activation-induced elevation of EMMPRIN on T cells in culture and in EAE mice, correspondent with reduced immune function and EAE CNS pathology.

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“…First, transcriptional inhibition of gelatinase B production is possible (Houde et al, 1996;Tremblay et al, 1995;McMillan et al, 1996). Remarkably, in the study of McMillan et al (1996), the anti-inflammatory theophylline derivative (CT-2519) (Norga et al, 1995) (Suomalainen et al, 1992;Paemen et al, 1996) (Proost et al, 1993), which stimulate gelatinase B release from recruited leukocytes and thus assist in the generation of a peritumoral protease load and in a countercurrent migration of cancer cells (Opdenakker and Van Damme, 1992b). Particular subsets of these chemokines possess angiogenic activities (Strieter et al, 1995).…”

mentioning

confidence: 99%

Proteinase inhibition in invasive cancer therapy: Four control levels of matrix degradation

Opdenakker¹,

Paemen²,

Norga³

et al. 1997

Int. J. Cancer

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Proteinase inhibition in invasive cancer therapy: four control levels of matrix degradation (Larsen, 1993;Fontanini et al., 1996). Second, the understanding of the control of proteolysis at the invasive front of a malignant tumor is rapidly growing and is generating concepts with practical implications for the treatment of cancer.The concept that particular proteases, e.g., plasminogen activators, contribute to invasion and metastasis is not new (reviewed by Danø et al., 1985;Murphy et al., 1989;Liotta and Stetler-Stevenson, 1991;Mignatti and Rifkin, 1993). Like the blood-clotting cascade, remodeling of the extracellular matrix at the invasion front is governed by a strictly regulated cascade of proteolytic enzymes (Woessner, 1991;Matrisian, 1992). Serine proteases and metalloproteases (e.g., collagenases, stromelysins, gelatinases) are examples of such enzymes. In Figure 1 (Opdenakker and Van Damme, 1992a). A high local protease load may be obtained by concentration of proteases on specific membrane receptors (Blasi, 1988;Emonard et al., 1992) or by anchoring through an intrinsic hydrophobic transmembrane domain (Sato et al., 1994;Puente et al., 1996).Recent studies illustrate that intervention at each of these levels promises to become a new target for cancer therapy. First, transcriptional inhibition of gelatinase B production is possible (Houde et al., 1996;Tremblay et al., 1995;McMillan et al., 1996). Remarkably, in the study of McMillan et al. (1996), the anti-inflammatory theophylline derivative (CT-2519) Paemen et al., 1996) interleukin-8 and granulocyte chemotactic protein-2 (Proost et al., 1993), which stimulate gelatinase B release from recruited leukocytes and thus assist in the generation of a peritumoral protease load and in a countercurrent migration of cancer cells (Opdenakker and Van Damme, 1992b). Particular subsets of these chemokines possess angiogenic activities (Strieter et al., 1995). Inhibition of such chemokines may, predictably, result in lower protease secretion levels and might reverse the invasive phenotype. was also shown to inhibit tumor-cell invasion. Since many proteases depend on transcriptional induction by cytokines, we may expect more results, of relevance for tumor-cell invasion control, from studies on anti-inflammatory drugs and cytokineinhibitors. In line with this, the control of endotoxinemia in patients with invasive cancers may be crucial. Endotoxin is a strong inducer of matrix proteases such as gelatinase B, interstitial collagenase and stromelysin, and also an inducer of many cytokines which are known to induce these enzymes. At the levels of activation and enzyme inhibition, antiinflammatory drugs also play a role. For instance, the antirheumatic, D-penicillamine, was found to inhibit gelatinase B (and A) and-at a higher dose-to inhibit the 2 plasminogen activators. This implies that D-penicillamine might block the activation of gelatinase B by the inhibition of plasminogen activitor or gelatinase A (Norga et al., 1995). At the same time, Dpenicillamine dire...

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The gelatinase inhibitory activity of tetracyclines and chemically modified tetracycline analogues as measured by a novel microtiter assay for inhibitors

Cited by 104 publications

References 23 publications

Targeting MMPs in Acute and Chronic Neurological Conditions

Targeting MMPs in Acute and Chronic Neurological Conditions

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

Proteinase inhibition in invasive cancer therapy: Four control levels of matrix degradation

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