| Summary: | 博士 === 中山醫學大學 === 生化暨生物科技研究所 === 95 === Metastasis, the major cause of cancer death and various treatment strategies have targeted on preventing the occurrence of metastasis, is a multi-step process involving cell adhesion and proteolytic degradation of the extracellular matrix (ECM), essential to achieving cell motility. Many bioactive properties of anthocyanins and flavonoid, present in various fruits and vegetables as natural colorants, have been well characterized. They are widely used for their antioxidant properties. Recent studies have also revealed pleiotropic anticancer and antiproliferative capabilities of anthocyanins. Berry extract contains high amounts of anthocyanins and is commonly used in certain diet and therapeutic applications. This study first demonstrates that, in the absence of cytotoxicity, black rice anthocyanoins (Oryza sativa L. anthocyanins (OAs), peonidin 3-glucoside, and cyanidin 3-glucoside), mulberry anthocyanins (mulberry anthocyanins (MACs), cyanidin 3-rutinoside, and cyanidin 3-glucoside), or silibinin exerted a dose-dependent inhibitory effect on the invasion, and motility of highly metastatic human lung cancer cells (A549 and H1299) and murine lung cancer cells (Lewis lung carcinoma; LLC). We examined the effect of anthocyanins on factors of cancer metastasis. We treated tumor cells with various concentrations of anthocyanins, for set periods, and then subjected cells to gelatin zymography, casein zymography, and Western blot to investigate the expression of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), urokinase-type plasminogen activator (u-PA), tissue inhibitor matrix metalloproteinase -2 (TIMP-2), and plasminogen activator inhibitor-1 (PAI-1). Following treatment with these compounds was found to decrease the expression of MMP-2, MMP-9, and u-PA in a concentration-dependent manner and enhance the expression of TIMP-2 and PAI-1. Further analysis with semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) showed that these alternations were all on the transcriptional levels. Further, a treatment of cyanidin 3-glucoside, peonidin 3-glucoside, or cyanidin 3-rutinoside also resulted in an inhibition on the activation of p-ERK1/2, c-Jun, c-Fos, or NF-κB and decreases the DNA binding activity. Overexpression with MEK1 blocked peonidin 3-glucoside and cyanidin 3 glucoside-inhibited H1299 cell invasion, amd suggests that the target point is the upstream of ERK 1/2. We also demonstrated that silibinin could significantly inhibit the invasion, motility, secretion of MMP-2 or u-PA of oral squamous cell
carcinoma (SCC-4) together with an enhanced expression of TIMP-2 and PAI-1. A treatment with silibinin also led to a dose-dependent inhibition on the activation of ERK1/2, NF-κB, c-Jun and c-Fos. Cyanidin 3-glucoside and peonidin 3-glucoside may exert a cell growth inhibitory through an arrest of G2/M phase of cell cycle, inhibition of cell
proliferation and induction of apoptosis in Hs578T human breast carcinoma cells. Treatment for OAs, cyanidin 3-glucoside, peonidin 3-glucoside, or silibinin suppressed the metastasis and tumor volume of LLC cells in C57BL/6 mice. Moreover, peonidin 3-glucoside and cyanidin 3-glucoside suppressed the tumor growth in H1299 xenograft
nude moce. Together, these results suggest that cyanidin 3-glucoside, peonidin 3-glucoside, or silibinin may act to decrease the in vitro protease expression of cancer cells and therefore, reduce the invasion and metastasis of tumor cells, while cyanidin 3-glucoside and peonidin 3-glucoside could inhibit breast cancer cells proliferation, and induce cell apoptosis. This study suggests a possible role for anthocyanins in cancer therapy.
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