Cancer Letters

Cancer Letters

Volume 158, Issue 1, 29 September 2000, Pages 85-91
Cancer Letters

Anti-proliferative effect of resveratrol, a natural component of grapes and wine, on human colonic cancer cells

https://doi.org/10.1016/S0304-3835(00)00511-5Get rights and content

Abstract

Resveratrol, a natural polyphenolic phytoalexine present in grapes and wines, has been reported to exert a variety of important pharmacological effects. We investigated the effects of resveratrol on the growth and polyamine metabolism of CaCo-2 human colon cancer cells. Treatment of the CaCo-2 cells with 25 μM resveratrol caused a 70% growth inhibition. The cells accumulated at the S/G2 phase transition of the cell cycle. No signs of cytotoxicity or apoptosis were detected. Resveratrol caused a significant decrease of ornithine decarboxylase (ODC) activity, a key enzyme of polyamine biosynthesis, which is enhanced in cancer growth. ODC inhibition resulted in the reduction of the intracellular putrescine content, indicating that polyamines might represent one of several targets involved in the anti-proliferative effects of resveratrol.

Introduction

Resveratrol (3,4,5′-trihydroxy-trans-stilbene), a natural polyphenol, is found in some plants that are used in human nutrition [1]. Grapes are a major source for resveratrol [2], and a significant amount can also be found in red wines [3]. In plants, resveratrol prevents fungal infection [1].

In several studies, strong antioxidant effects of resveratrol have been described [4], [5]. It is also an anti-mutagenic [6] compound, and a potent chemopreventive agent in a two-stage mouse skin cancer model [7]. Since it inhibits cyclooxygenase (COX) activities in different cancer models, resveratrol appears to act at the level of cancer promotion [7], [8], [9]. Its ability to inhibit the growth of several cancer cell lines [10], [11] and tumors [12] suggests that the compound may also have an inhibitory effect on cancer promotion/progression. Resveratrol seems to have a wide range of potential targets; however, the underlying mechanisms of its action are not well understood. Inhibition of ribonucleotide reductase [13], DNA polymerase [14], COX activities [8], [9], and of the cell cycle progression [15], [16] have been reported.

No information is at present available on the chemopreventive potentials of resveratrol on colon carcinogenesis. Therefore, we examined its effect on CaCo-2 cell growth, a human colonic cancer cell line. We also measured the effect of resveratrol on polyamine metabolism, which is known to be enhanced in cancer cells, and which might be one of the targets of the chemopreventive action of resveratrol [17].

Section snippets

Cell culture

CaCo-2 cells, obtained from the European Collection of Animal Cell Culture (CERDIC, Sophia Antipolis, France), were cultured in 75-cm2 Falcon flasks containing Dulbecco's modified Eagle's medium (DMEM) at 25 mM glucose supplemented with 10% heat-inactivated horse serum, 100 U/ml penicillin and 100 μg/ml streptomycin. Cells were incubated at 37°C in a humidified atmosphere of 5% CO2, and subcultured after trypsinization (0.5% trypsin/2.6 mM EDTA). They were used up to 30–40 passages. In the

Effects of resveratrol on CaCo-2 cell growth

Only a minor inhibition of CaCo-2 cell growth was observed in the presence of 5–20 μM resveratrol (Fig. 1). Growth was inhibited by more than 70% in cells exposed to 25–30 μM resveratrol. A concentration of 25 μM resveratrol was used in all further experiments.

In order to explore the basis of the anti-proliferative properties of resveratrol, cell cycle analyses were performed. The effect of resveratrol on CaCo-2 cell cycle phase distribution is shown in Fig. 2. A large proportion of the cells

Discussion

The present study shows that resveratrol, at a concentration of 25 μM, exhibits an important anti-proliferative effect on CaCo-2 cells. The anti-proliferative effect is related to the ability of resveratrol to provoke growth inhibition at the S/G2 phase transition of the cell cycle. Accumulation at the S/G2 phase transition [15] was also observed with HL-60 cells, and it was hypothesized that the effect was related to a decreased rate of DNA synthesis. Other observations suggested that

Acknowledgements

This work was supported by a grant from Ligue Nationale contre le Cancer (Comités départementaux du Bas-Rhin et du Haut-Rhin, France).

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