Flavonoid glycosides isolated from Salicornia herbacea inhibit matrix metalloproteinase in HT1080 cells Chang-Suk Kong a , You Ah Kim b , Moon-Moo Kim c , Jin-Sook Park d , Jung-Ae Kim d , Se-Kwon Kim d , Burm-Jong Lee e , Taek Jeong Nam f , Youngwan Seo b, * a Research Institute of Marine Science and Technology, Korea Maritime University, Busan 606-791, Republic of Korea b Division of Marine Environment and Bioscience, Korea Maritime University, Busan 606-791, Republic of Korea c Department of Chemistry, Dong-Eui University, Busan 614-010, Republic of Korea d Department of Chemistry, Pukyong National University, Busan 608-737, Republic of Korea e Department of Chemistry, Inje University, Gimhae 621-749, Republic of Korea f Faculty of Food Science and Biotechnology, Pukyong National University, Busan 608-737, Republic of Korea article info Article history: Received 3 April 2008 Accepted 24 July 2008 Available online 31 July 2008 Keywords: Salicornia herbacea Isorhamnetin 3-O-b-D-glucoside Quercetin 3-O-b-D-glucoside MMP-9 MMP-2 AP-1 abstract Flavonoid glycosides, isorhamnetin 3-O-b-D-glucoside, and quercetin 3-O-b-D-glucoside were isolated from Salicornia herbacea and their inhibitory effects on matrix metalloproteinase-9 and -2 (MMP-9 and -2) were evaluated in human fibrosarcoma cell line (HT1080). In zymography experiments, these flavo- noid glycosides led to the reduction of the expression levels and activities of MMP-9 and -2 without any significant difference between these flavonoid glycosides. Protein expression levels of both MMP-9 and MMP-2 were inhibited and TIMP-1 (tissue inhibitor of metalloproteinase-1) protein level was enhanced by these flavonoid glycosides. Moreover, a transfection study carried out with AP-1 reporter construct revealed that the reporter activity was suppressed by treatment with isorhamnetin 3-O-b-D-glucoside. Therefore, these results suggested that these flavonoid glycosides have a potential as valuable natural chemopreventive agents for cancer. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Matrix metalloproteinases (MMPs) are principal enzymes in extracellular matrix degradation and play a substantial role in path- ological processes including inflammation, arthritis, cardiovascular diseases, pulmonary diseases and cancer (Kohn et al., 1994; Nagase and Woessner, 1999; Benjamin, 2001; Wang et al., 2007). An excess of MMPs due to an imbalance between MMPs and naturally occur- ring MMP inhibitors is able to cleave most components of basement membrane and extracellular matrix (Rudek et al., 2002). Of the MMPs, gelatinase MMP-9 and MMP-2 have been explored exten- sively in tumor initiation and growth, invasion, angiogenesis, and metastasis in several cancers (McCawley and Matrisian, 2000; Brinckerhoff and Matrisian, 2002; Gomez et al., 1997; Brew et al., 2000; Ii et al., 2006). Elevated MMP-9 and MMP-2 levels in fibrosar- coma cells resulted in markedly enhanced metastasis potential (Bernhard et al., 1995; Kupferman et al., 2000). Therefore, much attention focused on development of MMP inhibitors as a new class of cancer therapeutic target. Especially recently, researchers have focused on finding biologically active compounds with possibilities as potential candidates for therapeutic effectiveness and functional food from natural resources. Halophytes are salt-resistant plants that are adapted to salinity stress. They are recognized environmentally as one of the most important ecosystems in a tidal zone since they play vital roles in the tidal ecology, such as serving as buffers, protecting the shorelines from erosion by the force of waves, and filtering contaminants from the land. However, recent studies have rarely addressed their biological activities as well as secondary metabo- lites (Jo et al., 2002; Bang et al., 2002; Han et al., 2003). Salicornia herbacea is one of the halophytes growing on salt marshes and muddy seashores along the western coast of Korea (Han et al., 2003). It has been used as a seasoned vegetable from coastal areas (Greenway and Munns, 1980) and a folk medicine for disorders such as constipation, obesity, diabetes, cancer, etc (Bang et al., 2002). Indeed, a number of investigators have reported antioxida- tive, antiinflamatory, immunomodulatory, antihyperglycemic, and antihyperlipidemic activities of S. herbacea (Seo et al., 2004; Im et al., 2003; Lee et al., 2006; Min et al., 2002; Bang et al., 2002). Park and Kim (2004) isolated the flavonoid glycosides, isorhamnetin 3-O-b-D-glucoside and quercetin 3-O-b-D-glucoside with DPPH (1,1Diphenyl-2-picrylhydrazyl) scavenging effect. However, studies on MMPs inhibition of these flavonoid glycosides have not been re- ported to date. 0887-2333/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tiv.2008.07.013 * Corresponding author. Tel.: +82 51 410 4328; fax: +82 51 404 3538. E-mail address: ywseo@hhu.ac.kr (Y. Seo). Toxicology in Vitro 22 (2008) 1742–1748 Contents lists available at ScienceDirect Toxicology in Vitro journal homepage: www.elsevier.com/locate/toxinvit