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

Abstract

Collagenase-3 (MMP-13) inhibitors have attracted considerable attention in recent years and have been developed as a therapeutic target for a variety of diseases, including cancer. Matrix metalloproteinases (MMPs) can be inhibited by a multitude of compounds, including hydroxamic acids. Studies have shown that materials and compounds containing trivalent metal ions, particularly potassium hexacyanoferrate (III) (K3[Fe(CN)6]), exhibit cdMMP-13 inhibitory potential with a half maximal inhibitory concentration (IC50) of 1.3μM. The target protein was obtained by refolding the recombinant histidine-tagged cdMMP-13 using size exclusion chromatography (SEC). The secondary structures of the refolded cdMMP-13 with or without metal ions were further analyzed via circular dichroism and the results indicate that upon binding with metal ions, an altered structure with increased domain stability was obtained. Furthermore, isothermal titration calorimetry (ITC) experiments demonstrated that K3[Fe(CN)6]is able to bind to MMP-13 and endothelial cell tube formation tests provide further evidence for this interaction to exhibit anti-angiogenesis potential. To the best of our knowledge, no previous report of an inorganic compound featuring a MMP-13 inhibitory activity has ever been reported in the literature. Our results demonstrate that K3[Fe(CN)6] is useful as a new effective and specific inhibitor for cdMMP-13 which may be of great potential for future drug screening applications.

Potent and selective inhibition of matrix metalloproteinases by lanthanide trichloride

“…However, most MT1-MMP inhibitors are organic compounds and antibody, and only few inorganic inhibitors have been reported. [19][20][21][22] Our previous work on the effect of trivalent Al and Fe on MMPs revealed that these trivalent metal salts and their complexes all signicantly affect the MMPs activity and the cell migratory and invasive capability. So we speculate that some other trivalent metal ions may also have the similar biological activity.…”

“…23 Reports indicated that the 3-valent lanthanide compounds affect tumor cell growth and MMP expression. 22,24,25 A study found that LaCl 3 exerts a concentration-dependent inhibitory effect on invasive tumor cells, and LaCl 3 (<50 mmol L À1 ) inhibits the activity and expression of pro-MMP-2 but does not suppress the activated form of MMP-2. 24 The inhibitory activities of different valence metal compounds demonstrate that the lanthanide elements (EuCl 3 , LaCl 3 , and PrCl 3 ) can inhibit the protein activity of cdMMP-13.…”

“…24 The inhibitory activities of different valence metal compounds demonstrate that the lanthanide elements (EuCl 3 , LaCl 3 , and PrCl 3 ) can inhibit the protein activity of cdMMP-13. 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 .…”

Elevated circulating magnesium levels in patients with Parkinson&rsquo;s disease: a meta-analysis

“…Metal homeostasis plays an important role in biological processes involved in signal transduction, cell respiration, metalloproteinase activity, and other physiological processions because of their ability to accept or donate electrons. 9 , 10 However, the imbalance of metal homeostasis in brain, such as zinc, copper, manganese, or iron, also had potentially dangers for the onset and progression of neurodegenerative diseases, including PD. 11 , 12 For instance, metals could catalyze the formation of reactive oxygen species, which caused oxidative stress leading to the death of dopaminergic neurons.…”

Spectroscopic Determination of Metal-Ligand Coordination by Biologically Active 2-Picolinehydroxamic Acid with Iron(III) and Oxidovanadium(IV) in Aqueous Solutions

“…[18][19][20] In addition, hydroxamic acids showing a strong interaction with metal ions have Woźniczka et al: Spectroscopic Determination of Metal-Ligand ... been used to treat anemia, remove excess iron ions and serve as inhibitors. 15,[21][22][23][24] They also arouse clinical interest related to the possible treatment of lung silicosis, and can be used as antimalarials and antibacterial agents. 25 Deferoxamine B, a siderophore produced by microorganisms, has been recognized as a strong vanadium chelator.…”