Inhibition of MMP Synthesis by Doxycycline and Chemically Modified Tetracyclines (CMTs) in Human Endothelial Cells

Abstract

Doxycycline is a commonly used broad-spectrum antibiotic. Recently, it has been shown that it also inhibits the activity of mammalian collagenases and gelatinases, an activity unrelated to its antimicrobial efficacy. In this study, we show that doxycycline not only inhibits MMP-8 and MMP-9 (gelatinase B) activity, but also the synthesis of MMPs in human endothelial cells. Doxycycline (50 microM) completely inhibited the phorbol-12-myristate-13-acetate (PMA)-mediated induction of MMP-8 and MMP-9, as measured by Western blotting and gelatin zymography, respectively. The inhibition was also observed at the mRNA level. No effect was observed on the expression of MMP-2 and of the MMP inhibitors TIMP-1 and TIMP-2. Chemically modified tetracyclines (CMTs) showed an inhibition similar to that of doxycycline, albeit less efficient. These observations demonstrate that endothelial cells display a specific regulation of MMPs, which may have implications for the pharmaceutical interaction in angiogenesis and angiogenesis-related diseases.

Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis

“…However it is not completely understood if the reduced number of metastases is due to a direct e ect of tetracyclines on MMP synthesis or on tumor cell proliferation. In this context studies on chemically modi®ed tetracycline type inhibitors on MMPs have shown that while MMPs can indeed be directly inhibited at the levels of transcription (Curci et al, 2000;Hanemaaijer et al, 1998) and function (Smith et al, 1999;Sorsa et al, 1998), many tumor and normal cell lines show a tetracycline-mediated growth inhibition which may be independent of the MMP blockade (Bettany and Wolowacz, 1998;Sledge, 1995, 1998;van den Bogert et al, 1985). This might explain the observation that doxycycline, administered at 20 mg/kg/day, signi®cantly inhibited tumor growth of mammary carcinoma cells subcutaneously injected in athymic mice (Fife and Sledge, 1998).…”

“…Doxycycline belongs to the family of chemically modi®ed tetracyclines, which can suppress MMP activity in a variety of tissues and tumors (Sipos et al, 1994), as well as inhibit gelatinase activity in human breast carcinoma cells (Fife and Sledge, 1995). Although doxycycline has been considered a nonselective MMP inhibitor, published data suggest that this chemically modi®ed tetracycline seems to preferentially inhibit gelatinase B/MMP9 activity and expression in corneal epithelial (Sobrin et al, 2000) and human endothelial cells (Hanemaaijer et al, 1998), as well as reducing in vivo levels of MMP-9 in tissues from patients with thoracic aneurysms (Curci et al, 2000). These observations prompted us to analyse the e ect of doxycycline on MMP synthesis and consequent tumor vascularization in normal and a1-null mice.…”

Sıçanlarda Doksisiklinin Kimyasal Peritonite Bağlı Peritoneal Fibrozis Gelişimi Üzerine Etkisinin İncelenmesi

“…Yapılan klinik ve deneysel çalışmalarda, periton dokusunda özellikle MMP-2, MMP-3, MMP-9, TIMP-1 ve TIMP-2 aktivitelerinin belirgin olduğu gösterilmiştir (7). Doksisiklin antimikrobiyal ve antiinflamatuvar etkiye sahiptir, aynı zamanda MMP inhibitörüdür (8). Literatürde bu antibiyotik grubunun MMP inhibisyonu ile ilgili deneysel hayvan çalışmaları bulunmaktadır (9), ancak kimyasal peritonite bağlı fibrozis gelişimi üzerine etkisi ile ilgili klinik ve deneysel hayvan çalışması yoktur.…”

Actual Pharmacological Treatment to Reduce Growth of Small Abdominal Aneurysm

“…This inhibition promotes the decrease of both protein and mRNA MMP levels that may affect endothelial cells migration during angiogenesis (Hanemaaijer et al,1998).…”