| Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are capable of hydrolyzing all known constituents of the extracellular matrix (ECM). MMPs are key regulators for many physiological and pathological functions. The MMP inhibitors have been shown to modulate pathological conditions associated with inflammation, cancer, cardiovascular diseases and neurodegenerative disorders.The pharmaceutical industry has made great effort to develop MMPIs over the past 20 years, primarily for the treatment of cancer. Most of the first generation anti-MMP drugs were designed as peptide mimics of the collagen amino-acid sequence near the collagenase cleavage site. MMP inhibitory compounds have also been derived by using information from three-dimensional structures of MMPs or large-scale screens to identify MMP inhibitory properties. Many of these molecules bind specifically to the zinc-binding site of these enzymes. However, these MMPIs have been failed in clinical trials of patients with late stage cancer. One reason was that these drugs were only tested in patients with advanced disease. Second, the MMPIs used in these studies were broad-spectrum drugs that also inhibited the MMP's anti-tumour effects. Third, a small number of patients in these studies also developed severe musculoskeletal side effects that forced their drug dose to be reduced to tolerable levels that were lower than minimal inhibitory concentrations, or for the patients to be removed from the trial. Therefore, people are increasingly seeking better health through complementary and alternative medicine. There is increased interest in finding anti-tumor agents derived from natural sources, as well as finding new MMP inhibitors. Currently, developing nature-derived MMPIs is among the strategies for seeking novel MMPIs.There is thousands years of history for traditional Chinese medicine (TCM) in China. Korean monkshood root (Guanbaifu in Chinese), as one of them, is the stem tuber of Aconitum coreanum (Levl.) Raipaics. In traditional Chinese medicine, Korean monkshood root is commonly used for treating arthralgia, headache, convulsive epilepsy, coronary heart disease, ischemic arrhythmia, pyocutaneous disease, and anemogenous phlegm. It has also been reported to treat arthritis and physical injuries such as fractures with good results.In this paper, Korean monkshood root have been isolated according to its MMP-16 inhibility. The purified active ingredient was identified by the elemental analysis, infrared spectrum (IR) and X-ray diffraction as aluminum ammonium sulfate dodecahydrate. This inorganic compound showed inhibitory activities toward a number of MMP family members, including MMP-16, MMP-13, MMP-2, MMP-3, and MMP-9. Moreover, it has a strong inhibitory effect toward MMP-2 and MMP-9, with IC50 values of 0.54μM and 0.50μM, respectively. Further more, the salts without Al3+ ions, regardless of SO42- salts or NH4- salts, showed no inhibitory effect on MMP-16. These data suggested that the active group of NH4Al(SO4)2·12H2O on MMP-16 was Al3-. Cell viability assays using human fibrosarcoma HT1080 cells showed aluminum ammonium sulfate had minimal cyto-toxicity with a concentration of up to 500μM. However, within 50μM, it exhibited significant inhibition of cell invasion of HT1080 cells in a dose-dependent manner. The inorganic non-chelator form of the MMP inhibitor with strong inhibitory activity has rarely been reported. Our results showed that aluminum ammonium sulfate is a novel, inorganic form of MMP inhibitor with high potency, and can be used to interfere with MMP related cellular processes. In summary, we isolated and identified the active compound in the water extracts of Korean monkshood root as aluminum ammonium sulfate dodecahydrate (NH4Al(SO4)2·12H2O), this is the first time that an inorganic non-chelator compond with high MMP inhibitory activity has been reported. We have also analyzed the active component in this compond and demonstrated the Al3+ in this compond is mainly responsible for the inhibition. Finally, we investigated its effect on cell invasion.
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