Aluminum ammonium sulfate dodecahydrate purified from traditional Chinese medicinal herb Korean monkshood root is a potent matrix metalloproteinase inhibitor

Abstract

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases and key regulators for many physiological and pathological functions. The MMP inhibitors have been shown to modulate diseases such as cancer, inflammation, and cardiovascular diseases. In this paper we tracked the MMP inhibitory activities of the traditional Chinese medicinal herb Korean Monkshood Root. 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. In particular, it has a strong inhibitory effect toward MMP-2 and MMP-9, with IC50 values of 0.54 and 0.50 μM, respectively. Further analysis suggested that the MMP inhibitory activity is mainly due to Al(3+). Cell viability assays using human fibrosarcoma HT1080 cells showed aluminum ammonium sulfate had minimal cyto-toxicity with a concentration up to 500 μM. However, within 50 μM, it exhibited significant inhibition of cell invasion. To our knowledge, there has been no previous report of inorganic form of the MMP inhibitor with strong inhibitory activity. Our results for the first time showed that aluminum ammonium sulfate is an inorganic form of MMP inhibitor with high potency, and can be used to interfere with MMP related cellular processes.

Potent and selective inhibition of matrix metalloproteinases by lanthanide trichloride

“…Given their antibacterial, antiviral, and antitumor activities, the 3-valent lanthanide compounds play an important role in disease-associated biological processes. [23][24][25][26][27] The interaction of the europium ion (Eu 3+ ) with the protein a-amylase, an important digestive enzyme in saliva and pancreatic juice, has been studied over wide ranges of pH and concentration. The protein provides three independent, noncooperative binding sites for Eu 3+ .…”

“…22 The antibacterial and antiviral activities of lanthanide element organic coordination compounds have also been investigated. 25 We previously showed that trivalent aluminum salts and iron salts exert inhibitory effects on MMPs and hinder the tumor migration and metastasis without affecting cell viability 26,27 . However, the inhibitory effects of the 3-valent lanthanide compounds on MT1-MMP and the protein's related diseases have been rarely explored.…”

Trivalent metal ions based on inorganic compounds with in vitro inhibitory activity of matrix metalloproteinase 13

“…This was the first time that an inorganic substrate, i.e. aluminum ammonium sulfate, has been demonstrated to exhibit MMP inhibitory activity, potent enough to interfere with MMP related cellular processes [31].Human matrix metallopeptidase 13 (MMP-13), also known as collagenase-3, represents a key member of the MMP family and has been identified as an important target for the treatment of osteoarthritis (OA) [32][33][34][35]. Until now, MMP-13 inhibitors have been identified mainly viahigh-throughput screening (HTS) in the synthetic compound library.…”

“…This was the first time that an inorganic substrate, i.e. aluminum ammonium sulfate, has been demonstrated to exhibit MMP inhibitory activity, potent enough to interfere with MMP related cellular processes [31].…”

“…Hydroxamic acid is a typical inhibitor for MMP-13 and the reaction mechanism for this activity has been suggested to be due to a functional group that is able to coordinate the central zinc(II) ion to two oxygen atoms via a bidentate ligand interaction [36][37][38][39]. In our previous work, Al 3+ has been shown to exhibit strong inhibitory effects on both MMP-2 and MMP-9 using a HT1080 cell line [31]. We are now interested to determine whether Al 3+ or other metal ions would exhibit similar effects on the catalytic domain in MMP-13 (cdMMP-13) in vitro.…”