Matrix Metalloproteinase Inhibitors as Prospective Agents for the Prevention and Treatment of Cardiovascular and Neoplastic Diseases

Abstract

Acting on a broad spectrum of extracellular, intracellular, and membrane-associated substrates, the matrix metalloproteinases (MMPs) are critical to the biological processes of organisms; when aberrantly expressed, many pathological conditions may be born or exacerbated. The prospect of MMP inhibition for therapeutic benefit in cancer, cardiovascular disease, and stroke is reviewed here. MMP inhibitor (MMPI) development constitutes an important branch of research in both academic and industrial settings and advances our knowledge on the structure-function relationship of MMPs. Targeting MMPs in disease treatment is complicated by the fact that MMPs are indispensable for normal development and physiology and by their multi-functionality, possible functional redundancy or contradiction, and context-dependent expression and activity. This complexity was revealed by previous efforts to inhibit MMP activity in the treatment of cancer patients that yielded unsatisfactory results. This review focuses on MMPI development since the late 90s, in terms of natural products and their derivatives, and synthetic compounds of low molecular mass incorporating specific zinc-binding groups (ZBGs). A few polyphenols and flavonoids that exhibit MMPI activities may have chemopreventive and neuro- and cardiovascular-protective effects. A new generation of potent and selective MMPIs with novel ZBGs and inhibition mechanisms have been designed, synthesized, and tested. Although only one collagenase inhibitor (Periostat, doxycycline hyclate) has been approved by the Food and Drug Administration as a drug for the treatment of periodontal disease, new hope is emerging in the form of natural and synthetic MMPIs for the prevention and treatment of stroke, cardiovascular disease, cancer, and other medical conditions.

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

“…In primary macrophages, MMP suppression may have been secondary to both inhibiting Mtb growth and reducing MMP expression, but in normal human bronchial epithelial and A549 cells the effect of doxycycline on MMP secretion, promoter activity, and mRNA accumulation was direct, because the CoMtb stimulus contained no live mycobacteria. Doxycycline is also an inhibitor of MMP activity (25). Consequently, doxycycline may reduce pathology in human TB by effects on both MMP gene transcription and activity.…”

“…Doxycycline is an antibiotic with broad spectrum MMP inhibitory activity and is the only licensed MMP inhibitor in the United States (25). Therefore, we examined whether doxycycline modulated MMP secretion driven by Mtb.…”

Exosite Interactions Impact Matrix Metalloproteinase Collagen Specificities

“…For the aforementioned collagenases, efficient catalytic activities toward collagens require both the CAT and HPX domains (11)(12)(13)(14)(15)(16)(17). Taking into account the importance of the CAT and HPX domains, the collagenolytic process has been proposed to involve discrete, sequential steps (17).…”

Abalone Haliotis discus hannai Intestine Digests with Different Molecule Weights Inhibit MMP-2 and MMP-9 Expression in Human Fibrosarcoma Cells

“…MMPs regulate the synthesis and secretion of cytokines, growth factors, hormone receptors and cell adhesion molecules. They also contribute to cell growth and development, cell morphogenesis, tissue remodelling, angiogenesis, cardiovascular, allergies, neurodegenerative diseases, some cancers, and a series of physiological and pathological processes (Sang et al, 2006;Hu et al, 2007;Kong et al, 2008).…”