Resveratrol suppresses hepatoma cell invasion independently of its anti-proliferative action
Introduction
An important and characteristic step of cancer metastasis is invasion [1]. The blockage of this biological event by drugs or food factors will prolong the life span of an affected host. Our previous research showed that extracts of teas and coffee and sera obtained from rats given either of these beverage extracts orally suppressed the invasion of rat ascites hepatoma AH109A cells in vitro [2], [3], [4], [5]. Since both teas and coffee include polyphenolic components with antioxidative activity, the results of these and other works led us to assume that widespread antioxidants suppress the invasion of cancer cells. We have actually demonstrated that certain carotenoids, food factors with antioxidative activity, inhibit the invasion of the hepatoma cells [6].
Resveratrol (3,5,4′-trihydroxy-trans-stilbene), present in grapes and other plants, is a phytoalexin with antioxidative activity. This compound has cancer chemopreventive activity [7] and suppresses tumor growth [8], [9]. Hsieh et al. [10] reported that resveratrol showed a greater anti-proliferative effect on highly invasive breast carcinoma cells (MDA-MB-435) than on minimally invasive cells (MCF-7). This report, however, did not describe anti-invasive activity of this compound.
In this study, the effect of resveratrol on the invasion of AH109A cells, a rat ascites hepatoma cell line, was investigated in a co-culture system of the hepatoma cells with mesentery-derived mesothelial cells (M-cells). Using AH109A cells pretreated with hypoxanthine (HX) and xanthine oxidase (XO), we attempted to demonstrate the importance of the antioxidative activity of resveratrol in inhibiting the tumor cell invasion.
Section snippets
Materials
Resveratrol (Sigma, St. Louis, MO) was dissolved in dimethyl sulfoxide (DMSO, Sigma). The resveratrol solution was added to the medium at the final DMSO concentration of 0.5%. The control medium contained 0.5% DMSO alone. All other reagents were of the best grade commercially available.
Culture of AH109A hepatoma cells
A rat ascites hepatoma cell line of AH109A cells was provided by the Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan. AH109A cells were maintained and cultured in Eagle's minimum
Results
The effect of resveratrol on the proliferation and invasion of AH109A cells was evaluated using in vitro assay systems. Resveratrol at 100 and 200 μM dose-dependently inhibited the AH109A proliferation, whereas at up to 50 μM the compound exerted little influence on the proliferation (Fig. 1A). On the other hand, this stilbene began to significantly inhibit the invasion of the tumor cells at 25 μM and thereafter continued to reduce it up to 200 μM in a dose-dependent manner (Fig. 1B).
To
Discussion
In this report, we studied the in vitro and ex vivo effect of resveratrol on the proliferation and invasion of AH109A cells. Resveratrol inhibited both the proliferation and invasion of the hepatoma cells at higher concentrations of 100 and 200 μM (Fig. 1). However, the compound suppressed the invasion at concentrations of 25 and 50 μM where it exerted no influence on the proliferation. Resveratrol-loaded rat serum also restrained only the invasion (Fig. 2, Fig. 3). These results suggest that
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research (K.Y.) from the Ministry of Education, Science, Sports and Culture of Japan.
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