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2nd Department of Medicine, J. W. Goethe University, 60590 Frankfurt/Main, Germany
2To whom correspondence should be addressed. E-mail: j.stein{at}em.uni-frankfurt.de.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • piceatannol • Caco-2 cells • cell cycle • colon cancer
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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) and an analog of the cancer chemopreventive agent resveratrol (trans-3,5,4'-trihydroxystilbene). Both substances are synthesized in plants in response to fungal or other environmental stress, classifying them as phytoalexins. Piceatannol has been identified as the active ingredient of Melaleuca leucadendron (white tea tree), Cassia garretiana (Asian legume) and Rheum undulatum (Korean rhubarb), which are used in traditional herbal medicine (1
–4
), and as the antileukemic compound in the seeds of Euphorbia lagascae, which is used in folk medicine to treat cancer, tumors and warts (5
). Teguo et al. (6
) detected piceatannol in cell suspension cultures of Vitis vinifera (wine grapes).
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). The molecule acts as an inhibitor of the focal adhesion kinase and Src in murine platelets (8
) and exerts an inhibitory effect on the catalytical subunit of rat liver protein kinase A and rat brain protein kinase C (9
). In addition, piceatannol potently reduces rat brain mitochondrial F0F1-ATPase activity (10
). It was demonstrated recently that the compound prevents interferon-
–induced Stat3, Stat5 and Jak1 phosphorylation in B and T lymphocytes as well as in primary fibroblasts and HeLa cells (11
). These results indicate that piceatannol interferes with neoplastic growth by modifying multiple cellular targets. The primary objective of the present study was to elucidate the underlying molecular mechanisms of the antiproliferative action of piceatannol. Because of the importance of positive and negative cell cycle regulators in carcinogenesis, we determined whether they can be modulated by piceatannol. The data demonstrated that piceatannol inhibits the growth of colorectal cancer cell lines and arrests Caco-2 cells in the S phase of the cell cycle.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The human colon cancer cell lines Caco-2 and HCT-116 were obtained from the American Type Culture Collection (ATCC, Rockville, MD). Caco-2 cells of passages 57–64 were cultured in Dulbecco’s modified Eagle medium and HCT-116 cells of passage 17 were cultured in McCoy’s 5A. Both cell lines were supplemented with 10% fetal calf serum, penicillin (1000 U/L) and streptomycin (1 mg/L) and incubated at 37°C under an atmosphere of 5% CO2 in air. A stock solution of piceatannol (Alexis Biochemicals, Grünberg, Germany) was prepared in dimethyl sulfoxide (DMSO)3
. The compound was added directly to cell cultures at the indicated concentrations, whereas untreated cells received the solvent alone (
0.1% DMSO). Cytotoxicity was excluded by lactate dehydrogenase (LDH) release assay (Roche Molecular Biochemicals, Mannheim, Germany).
Cell number.
Determination of cell numbers was carried out using a modification of the method of Matsubara et al. (12
). Briefly, cells were plated at a density of 7 x 103 cells/well in 96-well microtiterplates. Treatment with increasing concentrations of piceatannol was carried out for 24, 48 and 72 h (piceatannol-containing medium was changed after 48 h). At the end of the incubation period, the medium was removed and any adherent cells were fixed to the plate with 5% formaldehyde in PBS. The cells were then stained with a 0.5% aqueous solution of crystal violet followed by elution of the dye with 33% aqueous acetic acid. Absorbance at 570 nm was determined with a Tecan Spectrafluor Plus microplate reader (Tecan, Crailshaim, Germany) and the number of cells was determined from a standard curve of absorbance against cell numbers calculated from a mean of six experiments.
Western blot analysis.
Cells were seeded in 80 cm2 flasks and incubated with increasing concentrations of piceatannol (25–200 µmol/L) for 24 h. Western blot analysis using total protein extracts from cultured cells was performed as previously described (13
). Protein content was quantified with the Bio-Rad (Bio-Rad Laboratories, Munich, Germany) colorimetric assay. Reprobing of blots for expression of actin was done routinely. Antibodies against p27KIP1, cdc2, cyclin-dependent kinase (cdk)2, cdk4, cdk6, cyclin A, cyclin B1 and cyclin D1 were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). Anti-p21WAF1/CIP1 was purchased from Oncogene (Cambridge, MA) and anti-cyclin E from Pharmingen (Becton Dickinson, Heidelberg, Germany).
Incorporation of [3H]thymidine and [14C]leucine.
Caco-2 cells were seeded in 24-well plates (5 x 104/well). During treatment with piceatannol, cells were pulsed with 18.5 MBq/well [3H]thymidine and 0.925 MBq/well [14C]leucine (Amersham Pharmacia Biotech, Freiburg, Germany). Medium was discarded, monolayers were washed three times with PBS and the cellular macromolecules were precipitated using 5% trichloroacetic acid. The acid was aspirated, cells were washed with absolute methanol and formic acid (2.5 mol/L) was used to solubilize the precipitated macromolecules. Probes were transferred to scintillation vials, 3.0 mL scintillation fluid (Packard Biosciences, Groningen, Netherlands) was added and measurements were carried out with a liquid scintillation counter (Packard Instruments, Meridien, CT). Cellular protein concentrations were determined as described in the Western blot analysis section.
Determination of alkaline phosphatase (AP) activity.
Alkaline phosphatase activity was measured using p-nitrophenylphosphate as substrate according to the manufacturer’s instructions (Merck, Darmstadt, Germany). Before treatment, cells were seeded in 6-well plates at a density of 25 x 104/well and allowed to attach overnight. Cell lysates of Caco-2 cells treated for 1, 4, 8 or 12 d with 12.5 µmol/L piceatannol were analyzed in the assay. Cellular protein concentrations were determined as described in the Western blot analysis section. AP activity was calculated in units per milligram protein.
Cell cycle analysis.
Cells were seeded in 6-well plates at a density of 15 x 104/well 24 h before treatment; 24 h after treatment, they were washed with PBS and harvested by trypsinization (0.5 g/L trypsin 0.2 g/L EDTA solution, Gibco, Eggenstein, Germany). DNA contents of cells were measured using a DNA staining kit (CycleTEST PLUS DNA Reagent Kit, Becton Dickinson). Propidium iodide–stained nuclear fractions were obtained by following the kit protocol. Data were acquired using CellQuest Software (Becton Dickinson) with a FACScalibur (Becton Dickinson, Heidelberg, Germany) flow cytometry system using 10,000 cells per analysis. Cell cycle distributions were calculated using ModFit LT 2.0 software (Verity Software House, Topsham, ME).
Statistical analysis.
Data were expressed as means ± SD. Differences between two values were tested for statistical significance using the Student’s unpaired t test (SigmaPlot, SPSS Chicago, IL). A P-value < 0.05 was considered to indicate a significant difference.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). After 24 h of treatment, piceatannol (200 µmol/L) significantly reduced cell counts to 83.7 ± 2.9% of control values. After 72 h, the growth rate of cells decreased to 94.3 ± 1.5 and 60.0 ± 3.2% of the control level with 12.5 and 200 µmol/L piceatannol, respectively. A growth inhibitory effect was also demonstrated for the colorectal cancer cell line HCT-116. After 72 h, the growth rate of HCT-116 cells was 91.7 ± 2.2 and 58.3 ± 3.1% of the control level with 12.5 and 200 µmol/L piceatannol, respectively (Fig. 2
B).
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shows the effect of increasing concentrations of piceatannol on the proliferation of Caco-2 cells over a period of 24 h, when both thymidine and leucine uptake were measured and related to protein content of the cells. Treatment caused a dose-dependent inhibition of [3H]thymidine (75.5 ± 18.8, 61.3 ± 22.7, 54.8 ± 18.3, 39.9 ± 9.4 and 23.7 ± 4.8% of control, with 12.5, 25, 50, 100 and 200 µmol/L, respectively) and [14C]leucine incorporation (72.9 ± 15.1, 67.3 ± 14.8, 54.3 ± 15.2, 52.4 ± 9.5 and 48.8 ± 6.3% of control, with 12.5, 25, 50, 100 and 200 µmol/L, respectively). The effects were not associated with unspecific toxicity of the compound because LDH activity in the cell culture medium was unchanged after piceatannol treatment (data not shown). AP activity, a well-established marker of differentiation was assessed in Caco-2 cells, which differentiate spontaneously after 1 wk in culture. Assessment of AP activity was carried out after 4, 7 or 10 d of incubation with 5 µmol/L piceatannol. No significant effect on AP activity was observed under these conditions (data not shown).
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shows the sequence of these changes. Control cells revealed a distribution of cells in G0/G1 (36.39 ± 0.74%), in S (46.53 ± 0.65%), and G2/M (17.09 ± 1.38%) phases of the cell cycle. At 100 µmol/L, piceatannol led to an accumulation of cells in the S phase (76.23 ± 0.82% in S phase, 13.33 ± 0.22% in G0/G1, and 10.44 ± 1.03% in G2/M phase).
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, the proteins cdc2, cdk2 and cdk6 were constitutively present in Caco-2 cells incubated with piceatannol. Immunoblot analysis revealed a dose-dependent decrease in cyclin B1, cyclin D1, and cdk4 protein levels. Cyclin A protein expression was enhanced. The maximal effect was observed after the addition of 100 µmol/L piceatannol. We further examined the effect of piceatannol on the cyclin E abundance in Caco-2 cells. The protein was increased in a dose-dependent manner. Subsequently, we examined the expression of the cell cycle inhibitors p21WAF1/CIP1 and p27KIP1. A dose-dependent decrease of p27KIP1 was observed, whereas p21WAF1/CIP1 was unmodified after exposure to piceatannol. To ascertain whether piceatannol-induced effects on cell cycle regulating proteins was a general phenomenon or whether it was exclusive for Caco-2 cells, we investigated the effect of piceatannol on HCT-116 colon cancer cells. Our data show that after 24 h of exposure to 200 µmol/L piceatannol, protein levels of cyclin A, cyclin B1, cyclin D1, cdk4 and p27KIP1 were diminished, whereas the cyclin E level was enhanced (Fig. 6
).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–16
). Extensive in vitro cell culture studies have demonstrated this effect at the S to G2 phase transition with a decreased G0/G1 phase population in favor of an increase of cells in the S phase of the cell cycle (15
,17
–22
). Schneider et al. (22
) described these effects for the colorectal adenocarcinoma cell line Caco-2 after treatment with 25 µmol/L resveratrol. Most authors attributed the S phase arrest to an inhibition of ribonucleotide synthase and DNA synthesis, which have been demonstrated by Fontecave et al. (23
).
As shown by crystal violet assay, [3H]thymidine- and [14C]leucine-incorporation, piceatannol inhibits growth and proliferation of Caco-2 cells in a dose- and time-dependent manner. However, compared with resveratrol, the cytostatic effect is lower. Schneider et al. (22
) demonstrated >70% growth inhibition for 25–30 µmol/L resveratrol in Caco-2 cells. One of the mechanisms by which resveratrol exerts its antitumorigenic effects on cancer cells is inhibition of cyclooxygenases (COX) (24
). With respect to these data, we tested whether piceatannol affects growth of HCT-116 cells, which do not express COX-2 and lack COX-1 activity (25
,26
). Piceatannol also hampered growth of these cells, suggesting that the mechanism of growth inhibition is independent of COX activity.
Flow cytometry results revealed a reduction of Caco-2 cells in the G0/G1 and G2/M phases of the cell division cycle, whereas the S phase population increased. Data regarding resveratrol also demonstrated an increase of cells in the S phase (15
,17
–19
,21
22
,27
). We further examined expression of certain cell cycle–associated proteins. Western blot analysis of positive cell cycle regulators (cdc2, cdk2, cdk4, cdk6, cyclin A, cyclin B1, cyclin D1, and cyclin E) demonstrated a reduction of cyclin D1 levels and its related serine/threonine kinase cdk4 in Caco-2 cells as well as in HCT-116 cells. The cyclin D1/cdk4 complex mediates progression of the cell cycle in early G1 phase and inactivates the retinoblastoma protein (pRb), a tumor suppressor by phosphorylation (28
–29
). Negative control of cdk activity is exerted by inhibitors of cyclin-dependent kinases p21WAF1/CIP1 and p27KIP1 (30
), which are positive regulators of differentiation (31
). Whereas p21WAF1/CIP1 was unmodified by piceatannol addition, p27KIP1 levels were diminished in both cell lines tested. The cdk inhibitor p27KIP1 has its peak activity in G1 phase, whereas it is phosphorylated through the cyclin E-cdk2 complex in late G1 (32
) and afterwards subjected to ubiquitin-proteasome–dependent degradation (33
,34
). Treated Caco-2 cells progress over this restriction point with elevated cyclin E protein levels, which could account for the observed downregulation of p27KIP1. Another possible explanation is that expression of p27KIP1 is largely dependent on cyclin D1, especially in cyclin D1 overexpressing cells (35
,36
). Cyclin E mediates entry into S phase, whereas cyclin A accumulates later during S phase (29
). Piceatannol treatment led to a dose-dependent increase in cyclin E levels and an elevation of cyclin A levels in Caco-2 cells only at concentrations up to 100 µmol/L, suggesting the presence of an S phase arrest. Cyclin E protein expression of HCT-116 cells was also enhanced, whereas cyclin A was diminished. Similar changes in expression of cell cycle regulatory proteins were observed after incubation of Caco-2 cells with resveratrol (27
). Cyclin B is synthesized as a regulatory subunit of cdc2 as cells progress from S into G2/M phase (37
), and cdk2 is largely responsible for the induction of cyclin B observed at the G2/M transition (38
). Thus, the downregulation of cyclin B in piceatannol-treated cells likely reflects the inhibition of cdk2 activity. After exposure of Caco-2 cells to resveratrol, the same effect on cyclin B1 levels can be observed (data not shown).
These effects are specific for piceatannol and resveratrol because incubation of Caco-2 cells with the stilbene derivatives rhapontin and stilbene-methanol did not mimic the effects of resveratrol and piceatannol on S phase arrest (27
).
Our data showed for the first time that piceatannol suppresses growth by perturbing progression through the S phase. These effects could be mediated by the upregulation of positive cell cycle regulators, cyclin E and A, which reach their maximal activity and protein levels in the S phase of the cell cycle (39
,40
). At the same time, G0/G1 phase–regulating proteins, cyclin D1, cdk4 and p27KIP1, and G2/M regulating cyclin B1 are expressed at lower levels. Although the growth inhibition exerted by piceatannol is not as pronounced as the cytostatic effect of resveratrol, piceatannol seems to induce the same changes in cell cycle distribution and cell cycle regulatory proteins. The amount of cells that accumulate in the S phase of the cell cycle is even higher than that observed after addition of resveratrol.
Plant polyphenols such as genistein, quercetin, curcumin and green tea polyphenols cause growth inhibition either by arresting cells in G0/G1 phase or in G2/M phase (41
–44
). There is evidence that colon carcinoma cells arrested in G0/G1 phase are less susceptible to chemotherapeutics, which has been attributed to elevated p27Kip1 expression (45
). It is tempting to speculate that piceatannol, as a molecule that downregulates p27Kip1 and arrests cells in the S phase, might be utilized to enhance the effect of chemotherapeutic drugs that exert their effects specifically in the S phase of the cell cycle, like 5-fluorouracil, which is used to treat colon carcinoma. However, further studies are warranted to specify the effects of piceatannol and evaluate whether it can be used as an anticancer drug.
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FOOTNOTES |
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3 Abbreviations used: AP, alkaline phosphatase; cdk, cyclin-dependent kinase; COX, cyclooxygenase; DMSO, dimethyl sulfoxide; LDH, lactate dehydrogenase; pRb, retinoblastoma protein
Manuscript received 29 June 2001. Initial review completed 7 September 2001. Revision accepted 12 November 2001.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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 M Maggiolini, A G Recchia, D Bonofiglio, S Catalano, A Vivacqua, A Carpino, V Rago, R Rossi, and S Ando The red wine phenolics piceatannol and myricetin act as agonists for estrogen receptor {alpha} in human breast cancer cells J. Mol. Endocrinol., October 1, 2005; 35(2): 269 - 281. [Abstract] [Full Text] [PDF]
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 F. Wolter, S. Ulrich, and J. Stein Molecular Mechanisms of the Chemopreventive Effects of Resveratrol and Its Analogs in Colorectal Cancer: Key Role of Polyamines? J. Nutr., December 1, 2004; 134(12): 3219 - 3222. [Abstract] [Full Text] [PDF]
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 M. C. Lazze, M. Savio, R. Pizzala, O. Cazzalini, P. Perucca, A. I. Scovassi, L. A. Stivala, and L. Bianchi Anthocyanins induce cell cycle perturbations and apoptosis in different human cell lines Carcinogenesis, August 1, 2004; 25(8): 1427 - 1433. [Abstract] [Full Text] [PDF]
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 M. Swanson-Mungerson, M. Ikeda, L. Lev, R. Longnecker, and T. Portis Identification of latent membrane protein 2A (LMP2A) specific targets for treatment and eradication of Epstein-Barr virus (EBV)-associated diseases J. Antimicrob. Chemother., August 1, 2003; 52(2): 152 - 154. [Full Text] [PDF]
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F. Wolter, L. Turchanowa, and J. Stein Resveratrol-induced modification of polyamine metabolism is accompanied by induction of c-Fos Carcinogenesis, March 1, 2003; 24(3): 469 - 474. [Abstract] [Full Text] [PDF]
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F. Wolter and J. Stein Resveratrol Enhances the Differentiation Induced by Butyrate in Caco-2 Colon Cancer Cells J. Nutr., July 1, 2002; 132(7): 2082 - 2086. [Abstract] [Full Text] [PDF]
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