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ORIGINAL RESEARCH ARTICLE

Allyl Isothiocyanate and Its N-Acetylcysteine Conjugate Suppress Metastasis via Inhibition of Invasion, Migration, and Matrix Metalloproteinase-2/-9 Activities in SK-Hep1 Human Hepatoma Cells

School of Agricultural Biotechnology and Center for Agricultural Biomaterials, College of Agriculture and Life Sciences, Seoul National University, Shillim-dong, Gwanak-gu 151-742, Republic of Korea

To whom requests for reprints should be addressed at ¹ Department of Food Science and Technology, School of Agricultural Biotechnology and Center for Agricultural Biomaterials, College of Agriculture and Life Sciences, Seoul National University, San 56-1, Shillim-dong, Gwanak-gu, Seoul 151-742, Republic of Korea. E-mail: leehyjo{at}snu.ac.kr

Cruciferous vegetables contain a series of relatively unique secondary metabolites of amino acids, called glucosinolates. Sinigrin, the predominant aliphatic glucosinolate in cruciferous vegetables, is hydrolyzed to yield allyl isothiocyanate (AITC), which, after absorption and metabolism in humans, is excreted in the urine as an N-acetylcysteine (NAC) conjugate. We have determined the inhibitory effects of AITC and its NAC conjugate on cell proliferation, the expression of matrix metalloproteinases (MMPs), adhesion, invasion, and migration in SK-Hep1 human hepatoma cells. Our results demonstrate that AITC and NAC-AITC suppress SK-Hep1 cell proliferation in a dose-dependent manner; by 25% and 30% for 10 µM AITC and 10 µM NAC-AITC, respectively. We examined the influence of AITC and NAC-AITC on the gene expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). Gelatin zymography also revealed a significant downregulation of MMP-2/-9 expression in SK-Hep1 cells treated with 0.1–5 µM AITC and NAC-AITC compared with controls. Reverse transcriptase polymerase chain reaction revealed dose-dependent decreases in MMP-2/-9 messenger RNA levels in both AITC-treated and NAC-AITC–treated cells. TIMP-1/-2 activities were unaffected by treatment with AITC or NAC-AITC in our experiments. NAC-AITC inhibited cancer cell adhesion and invasion much more potently than its parent compound. NAC-AITC at 5 µM caused excellent inhibition of cell migration for 48 hrs. These results demonstrate the potential of AITC and NAC-AITC as chemopreventive agents.

Key Words: allyl isothiocyanate • sinigrin • N-acetylcysteine • SK-Hep1 cells • adhesion • invasion • migration • metastasis • matrix metalloproteinase • tissue inhibitors of metalloproteinase

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