Inhibition of MMP-3 activity and invasion of the MDA-MB-231 human invasive breast carcinoma cell line by bioflavonoids

Abstract

IntroductionMetastatic invasion is the primary cause of patient mortality during breast cancer progression. For a transformed cell to metastasize to a distant site in the body, it must first lose adhesion, penetrate and invade the surrounding extracellular matrix (ECM), enter the vascular system, and adhere to distant organs [1] . The inhibition of invasion of cancer cells has been an important strategy in cancer treatment [2] . A crucial step in the invasive processes is the proteolytic degradation of the ECM and basal membranes [3] . Several studies have shown that among the enzymes responsible for ECM degradation, the matrix metalloproteinases (MMPs) appear to play a critical role [4][5][6] . MMPs are zinc-dependent endopeptidases, which collectively can degrade all constituents of the ECM. Based on their structure and substrate specificity, they can be divided into subgroups of collagenases, stromelysins, gelatinases, membrane-type MMPs and other MMPs [7] .Breast cancer is the major cause of malignancy-related deaths of women worldwide. In Thailand, breast cancer is the second most common cancer among women and its incidence is increasing [8] . Cancer invasion and metastasis are leading causes of morbidity and mortality in patients with breast cancer. Several studies have demonstrated that upregulation of MMP-1, -2, -3, -7, -9, -13, and -14 is associated with breast cancer cell invasion [9][10][11] .MMP-3, also designated stromelysin 1, is a member of the matrixin family, which plays a pivotal role in the degradation and remodeling of the ECM. MMP-3 degrades several components of the ECM, such as fi bronectin, laminin, collagen type IV [12][13][14] and proteoglycans, and is thought to play an important role in rheumatoid arthritis, osteoarthritis [15,16] , tumor cell invasion and metastasis [17] . Aim: Stromelysin 1 (matrix metalloproteinase 3; MMP-3) is an enzyme known to be involved in tumor invasion and metastasis. In this study, fl avonoids from vegetables and fruits, such as quercetin, kaempferol, genistein, genistin, and daidzein, were tested for their ability to modulate the secretion and activity of MMP-3 in the MDA-MB-231 breast cancer cell line. In addition, we investigated the in vitro effects of fl avonoids on MDA-MB-231 cell invasion. Methods: The toxic concentration range of fl avonoids was evaluated using the MTT assay. The ability of MDA-MB-231 cells to invade was evaluated using a modifi ed Boyden chamber system. The activity of MMP-3 was determined by casein zymography. The secretion of MMP-3 was evaluated using Western blotting, casein zymography and confi rmed by ELISA. Results: Some putative fl avonoids, ie, quercetin and kaempferol (fl avonols), signifi cantly inhibited the in vitro invasion of MDA-MB-231 cells in a concentration-dependent manner, with IC 50 values of 27 and 30 μmol/L, respectively. Quercetin and kaempferol also reduced MMP-3 activity in a dose-dependent manner, with IC 50 values in the range of 30 μmol/L and 45 μmol/L, respectively. None of the fl avonoids had a signif...

Effects of Flavonoids on Matrix Metalloproteinase-13 Expression of Interleukin-1β–Treated Articular Chondrocytes and Their Cellular Mechanisms: Inhibition of c-Fos/AP-1 and JAK/STAT Signaling Pathways

“…We also investigated the suppressive mechanisms of MMP-1 down-regulation by naturally-occurring flavonoids in human dermal fibroblasts (14). Recently, it was also found that quercetin and kaempferol reduced MMP-3 activity in breast carcinoma cells (15).…”

Galangin and Kaempferol Suppress Phorbol-12-Myristate-13-Acetate-Induced Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma HT-1080 Cells

“…Some flavonols have been reported to control the function of specific MMPs by inhibiting their catalytic activity (Phromnoi et al, 2009;Sartor et al, 2002). Recently, we also found that one flavonol, fisetin, inhibits the catalytic activity of various MMPs, including MMP-14, and reduces MMP-dependent cellular processes, such as tumor cell invasion and endothelial cell tube formation .…”

Arsenic-Induced Hepatic Toxicity and Its Attenuation by Fruit Extract of Emblica officinalis (Amla) in Mice

“…Recent studies have suggested that the aqueous extract of amla was effective in preventing the invasion of MDAMB-231 cells in the in vitro matrigel invasion assay [38]. The amla phytochemical, kaempferol, inhibited the expression of stromelysin1 (MMP-3) in the MDA-MB-231 breast cancer cell line [39]. The polyphenol gallic acid is also reported to possess inhibitory effects on gastric adenocarcinoma cell migration, decreased expression of MMP-2/9 in vitro [40], It has been shown to exhibit a variety of biological activities including ant-oxidative activity [41].…”