Differential Inhibition of Matrix Metalloproteinases-2, -9, and -13 Activities by Selected Anthraquinones

Abstract

Matrix metalloproteinases (MMPs) play an important role in physiological and pathological matrix remodeling. Here, we report that the natural anthraquinones, emodin, emodic acid, chrysazin, physcion, and rhein differentially inhibit several members of this enzyme family, the gelatinases MMP-2 and -9, and the collagenase MMP-13. The IC₅₀ values determined by measuring the activities of human recombinant catalytic domains of these enzymes varied in the micromolar range. Emodin and emodic acid most potently inhibited MMP-9 with IC₅₀ values of 15 and 10 μM, respectively. With MMP-13, emodic acid was 3-times less potent than emodin which showed a similar IC₅₀ value (13 μM) as chrysazin. These results are of interest in view of the widespread medicinal use of anthraquinones and their derivatives.

Abbreviations

DMSO:dimethyl sulfoxide

MMP:matrix metalloproteinase

TIMP:tissue inhibitor of matrix metalloproteinases

Key words

anthraquinones - emodin - inhibition - matrix metalloproteinases

References

• 1 Malemud C J. Matrix metalloproteinases (MMPs) in health and disease: an overview.  Front Biosci. 2006;  11 1696-701
• 2 Hobeika M J, Thompson R W, Muhs B E, Brook P C, Gagne P J. Matrix metalloproteinases in peripheral vascular disease.  J Vasc Surg. 2007;  45 849-57
• 3 Murphy G, Nagase H. Reappraising metalloproteinase in rheumatoid arthritis and osteoarthritis: destruction or repair?.  Nat Clin Pract Rheumatol. 2008;  4 128-35
• 4 Manicone A M, McGuire J K. Matrix metalloproteinases as modulators of inflammation.  Semin Cell Dev Biol. 2008;  19 34-41
• 5 Clark I M, Swingler T E, Sampieri C L, Edwards D R. The regulation of matrix metalloproteinases and their inhibitors.  Int J Biochem Cell Biol. 2008;  40 1362-78
• 6 Bachmeier B E, Iancu C M, Jochum M, Nerlich A G. Matrix metalloproteinases in cancer: comparison of known and novel aspects of their inhibition as a therapeutic approach.  Expert Rev Anticancer Ther. 2005;  5 149-63
• 7 Gebhardt R. Oxidative stress, plant-derived antioxidants and liver fibrosis.  Planta Med. 2002;  68 289-96
• 8 Ende C, Gebhardt R. Inhibition of matrix metalloproteinase-2 and -9 activites by selected flavonoids.  Planta Med. 2004;  70 1006-8
• 9 Tamura T, Kosaka N, Tshiwa J, Sato T, Nagase H, Ito A. Rhein, an active metabolite of diacerhein, down-regulates the production of pro-matrix metalloproteinases-1, -3, -9 and -13 and up-regulates the production of tissue inhibitor of metalloproteinase-1 in cultured rabbit articular chondrocytes.  Osteoarthr Cartil. 2001;  9 257-63
• 10 Gui M, Zhang Y F, Xiao Z Y, Sun P, Dai J F, Wang S F. Inhibitory effect of emodin on tissue inhibitor of metalloproteinases-1 (TIMP-1) expression in rat hepatic stellate cells.  Dig Dis Sci. 2007;  52 200-7
• 11 Legendre F, Bogdanowicz P, Martin G, Domagala F, Leclercq S, Pujol J P. Rhein, a diacerhein-derived metabolite, modulates the expression of matrix degrading enzymes and the cell proliferation of articular chondrocytes by inhibiting ERK and JNK-AP-1 dependent pathways.  Clin Exp Rheumatol. 2007;  25 546-55
• 12 Raimondi L, Banchelli S G, Buffoni F, Ignesti G, Massacesi L, Amaducci L. Rhein and derivatives. In vitro studies on their capacity to inhibit certain proteases.  Pharm Res Commun. 1982;  14 103-12
• 13 Tanaka T, Metori K, Mineo S, Matsumoto H, Satoh T. Studies on collagenase inhibitors. Effects of anthraquinones on bacterial collagenase.  Yakugaku Zasshi. 1990;  110 688-92
• 14 Takano S, Gately S, Jiang J B, Brem S. A diaminoanthraquinone inhibitor of angiogenesis.  J Pharmacol Exp Ther. 1994;  271 1027-33
• 15 Galardy R E, Cassabonne M E, Giese C, Gilbert J H, Lapierre F, Lopez H. Low molecular weight inhibitors in corneal ulceration.  Ann N Y Acad Sci. 1994;  732 315-23
• 16 Barrabtes E, Guinea M. Inhibition of collagenase and metalloproteinases by aloins and aloe gel.  Life Sci. 2003;  72 843-50
• 17 Nissler L, Gebhardt R, Berger S. Flavonoid binding to a multi-drug-resistance trnasporter protein: an STD-NMR study.  Anal Bioanal Chem. 2004;  379 1045-9
• 18 Song R, Xu F, Zhang Z, Liu Y, Dong H, Tian Y. Structural elucidation of in vitro metabolites of emodin by liquid chromatography-tandem mass spectrometry. Biomed Chromatogr 2008; Doi: 10.1002/bmc.1050
• 19 Debord P, Louchahi K, Tod M, Cournot A, Perret G, Petitjean O. Influence of renal function on the pharmacokinetics of diacerein after a single oral dose.  Eur J Drug Metab Pharmacokinet. 1994;  19 13-9
• 20 Pavelka K, Trc T, Karpas K, Vitek P, Sedlackova M, Vlasakova V. The efficacy and safety of diacerein in the treatment of painful osteoarthritis of the knee: a randomized, multicenter, double-blind, placebo-controlled study with primary end points at two month after the end of three-month treatment period.  Arthritis Rheum. 2007;  56 4055-64
• 21 Teich L, Daub K S, Krügel V, Nissler L, Gebhardt R, Eger K. Synthesis and biological evaluation of new derivatives of emodin.  Biol Med Chem. 2004;  12 5961-71