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*
Division of Hematology and Oncology, and the
Department of Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, MI 48202
2To whom correspondence should be addressed. E-mail: sgotam{at}msn.com.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • resveratrol • apoptosis • antileukemic activity
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,2
). A number of food components have been identified that inhibit the initiation and progression of cancer or otherwise influence the potential for disease outcome (3
–5
). The beneficial effects of these dietary compounds have been attributed partly to the presence in food materials of numerous polyphenolic compounds with antioxidant and free radical scavenging properties (6
,7
). This conclusion is supported by epidemiological studies showing a close association between low incidence of coronary heart disease (the French paradox) and breast cancer (8
–10
) and moderate consumption of red wine containing natural polyphenolic compounds.
Resveratrol is a nonflavonoid polyphenolic compound found in grapes and red wine made from them. Resveratrol has been shown to modulate lipoprotein metabolism (11
,12
), eicosanoid synthesis (13
–15
), lipid oxidation (16
), and platelet aggregation (13
,17
). Resveratrol also suppresses the induction of nitric oxide synthase and disrupts arachidonic acid metabolism by inhibiting cyclooxygenase-2 (18
,19
). Recently, resveratrol was shown to inhibit cellular processes associated with tumor initiation, promotion, and progression in vivo, and the development of preneoplastic lesions in mouse mammary glands in vitro (20
). In other studies, resveratrol inhibited the proliferation of breast, oral, liver, prostate, and colon cancer cell lines in a dose- and time-dependent manner (21
–24
). Resveratrol has also shown cardioprotective and neuroprotective activities in rats (25
,26
).
We have previously reported that although resveratrol inhibits the growth of both normal hematopoietic progenitor cells and leukemia cell lines in a dose-related manner, the antiproliferative effect of resveratrol on normal hematopoietic progenitor cells is less dramatic and reversible compared to leukemia cells (27
). Resveratrol induced apoptosis in leukemia cells, but not in normal hematopoietic cells. Additionally, hematopoietic progenitor cells treated with resveratrol maintained their capacity to hematologically reconstitute lethally irradiated mice. Recently, we have also reported that resveratrol inhibits the proliferation of lymphocytes, development of T cell-mediated cytotoxicity, and cytokine secretion by affecting the activation and translocation of transcription factor NF-kB (28
). In contrast to a large number of studies demonstrating the antiproliferative effects of resveratrol on several tumor cell lines in vitro, very little is known about the antitumor activity of resveratrol in vivo. A few studies in which the antitumor effect of resveratrol on tumor growth in vivo was investigated, employed solid tumors only (29
,30
). The in vivo antitumor effect of resveratrol against hematologic tumors has not been studied. In this study, the antileukemic activity of resveratrol was examined using 32Dp210 cells, a mouse myeloid leukemia cell line. The results demonstrate that despite strong antiproliferative and apoptotic effects of resveratrol on 32Dp210 leukemia cells in vitro, resveratrol has only a weak if any antileukemic activity in vivo.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Eight- to 10-wk-old male C3H (H-2k) mice were purchased from the Taconic Laboratories (Germantown, NY). Mice consumed Teklad Mouse Breeder Diet (W) 8626 (protein, 20.0%; fat, 10.0%; and fiber, 3.0%) and water ad libitum in the Bioresource Facility of the Henry Ford Health System. They were housed for at least 1 wk before experimental use and age-matched mice were used within any given experiment. The treatment of mice and all experimental protocols were according to the Institutional Animal Care and Use Committee guidelines.
Agents.
Trans-resveratrol (trans-3,4',5-trihydroxy stilbene) was purchased from Sigma Chemical (St. Louis, MO). For in vitro experiments, a 100 mmol/L solution of resveratrol was prepared in DMSO and all test concentrations were prepared by diluting the appropriate amounts of stock solution in tissue culture medium. For oral administration, resveratrol suspension in water was prepared at 2 g/L. Oral administration was performed by using a 20-G ballpoint oral feeding needle (Popper and Sons, New Hide Park, NY).
Tissue culture medium.
All in vitro cell cultures were carried out in RPMI-1640 medium (Grand Island Biological Company, Grand Island, NY), supplemented with 10% fetal calf serum (Hyclone, Logan, UT), 1% penicillin/streptomycin, and 25 mmol/L HEPES buffer.
Cell lines.
Murine myeloid leukemia cell line 32Dp210, which was derived by transfecting myeloid progenitor cell line 32Dcl3 with BCR/ABL oncogene, was obtained from Dr. D. H. Fowler of the National Cancer Institute (Bethesda, MD). 32Dp210 leukemia cells were maintained in RPMI-1640 tissue culture medium by passaging 1 x 106 cells in 10 mL of culture medium at 4-d intervals.
Clonal growth assay.
The effect of resveratrol on leukemia cell proliferation was measured in a clonogenic assay. For clonal expansion, 5 x 102 leukemia cells were suspended in 1 mL of complete RPMI-1640 culture medium containing 0.3% agar. Cell suspensions with or without known concentrations of resveratrol, were plated (1 mL each) in 35-mm plastic Petri dishes in duplicate. Petri dishes were incubated at 37°C in humidified and 5% CO2 atmosphere for 7 d. Dishes were scored for colonies (>50 cells) under an inverted microscope.
Flow cytometric analysis.
Cells (1 x 106) were washed in PBS/EDTA/BSA buffer (PBS, 1 mmol/L EDTA, and 1 g/L BSA) and fixed in 100 µL of PBS/EDTA/BSA buffer + 900 µL of 70% ethanol at 4°C for 1 h. Cells were washed with PBS/BSA buffer and resuspended in 250 µL of 11.2 g/L sodium citrate buffer (pH 8.4) containing DNase free RNase A. Incubation was continued at 37°C for 30 min. Cellular DNA was stained by adding 250 µL of propidium iodide solution (50 g/L) for 30 min at room temperature. The stained cells were analyzed by fluorescent activated cell sorting (FACS) on a FACScan flow cytometer for relative DNA content based on red fluorescence.
DNA fragmentation.
To determine whether resveratrol induces apoptosis, 6 x 106 leukemia cells were treated with resveratrol (25, 50 or 100 µmol/L) for 16 h. After treatment, cells were washed with PBS and then lysed in cold lysis solution (5 mmol/L of Tris, pH 7.4, 20 mmol/L of EDTA, 0.5% Triton X-100) for 20 min. Cell lysates were centrifuged at 27,000 x g for 15 min, and DNA was extracted from the aqueous phase with phenol:chloroform:isoamyl alcohol (25:24:1, by volume) containing 0.1% hydroxyquinoline. DNA was precipitated with 0.3 mol/L of sodium acetate and 2 volumes of cold 100% ethanol. DNA specimens isolated from equal numbers of untreated and treated cells were fractionated on 1.2% agarose gel in Tris-acetate (0.04 mol/L Tris-acetate, 0.001 mol/L EDTA) electrophoresis buffer. After fractionation of DNA, gels were treated with RNase (20 mg/L) for 3 h and stained with ethidium bromide. In some experiments, apoptosis was determined by measuring internucleosomal DNA fragmentation by using a cell death detection ELISA kit (Cell Death Detection ELISA Plus; Roche Molecular Biochemicals, Indianapolis, IN) according to the instructions provided by the manufacturer.
Polymerase chain reaction (PCR).
Genomic DNA from the bone marrow of mice injected with 32Dp210 leukemia cells was isolated by using DNAzol (GIBCO BRL, Gaithersburg, MD). To detect BCR/ABL oncogene, 1µg of DNA was amplified by using a 5' primer corresponding to a BCR gene exon 2 sequence (5'-CAC AGC ATT CCG CTG ACC ATC-3') and a 3'-primer corresponding to a c-ABL exon 2 sequence (5'-GCT TCA CAC CAT TCC CCA TTG-3') that generate a 325-bp PCR product. Amplification was carried out for 30 cycles of denaturation (94°C for 1 min), annealing (59°C for 30 s), and polymerization (72°C for 30 s). The PCR products were fractionated by 1.5% agarose gel electrophoresis and visualized by ethidium bromide staining.
Statistical methods.
All values are expressed as means ± SEM. Colony counts were analyzed using a Kruskal-Wallis test and the significance of differences was determined by Wilcoxon rank sum tests. Kaplan-Meier survival curves were generated for survival data and comparisons were made using log rank tests. Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Whether the proliferation of 32Dp210 leukemic cells is affected by resveratrol was examined by measuring the effect of different concentrations of resveratrol (6.25–100 µmol/L) on the clonal expansion of these cells in vitro. The desired concentration of resveratrol was incorporated in culture medium containing 0.3% agar and was constantly present during the entire period of incubation of cultures. Figure 1
shows the dose-response effect of resveratrol on the clonogenic growth of leukemia cells. Resveratrol inhibited the proliferation of leukemia cells in a dose-related manner. The maximum suppression of clonal expansion (> 99%) occurred at 100 µmol/L resveratrol. There was 
90% and 53% suppression of colony development at 50 and 25 µmol/L resveratrol, respectively. Lower concentrations of resveratrol (e.g., 6.25 and 12.5 µmol/L) were noninhibitory (P = 0.309–0.149). At higher concentrations (e.g., 50 and 100 µmol/L), the number of colonies was significantly reduced (P = 0.021), and a few leukemic colonies that developed at these concentrations of resveratrol were smaller in size and reduced in cellularity compared with the colonies formed by untreated cells. The IC50 of resveratrol for 32Dp210 cells was 23 µmol/L. The inhibitory effect of resveratrol on leukemia cells was not due to DMSO used for dissolving resveratrol because equivalent concentrations of DMSO alone had no effect on the clonal expansion of these cells (data not shown). To determine whether the antiproliferative effect of resveratrol on 32Dp210 is reversible or irreversible, cells were treated with 50 µmol/L resveratrol for 16 h and were washed three times in PBS before initiating the clonal cultures. The growth suppressive effect of resveratrol on 32Dp210 cells was irreversible, because there was no improvement in the development of leukemic colonies after the removal of resveratrol (P = 0.559; Fig. 1
; 50/wash vs. 50 µmol/L).
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To determine the mechanism by which resveratrol inhibits the colonal growth, we examined whether resveratrol induces program cell death in 32Dp210 cells. To quantitate cell death by resveratrol, 32Dp210 cells were treated with 50 µmol/L resveratrol from 6 to 72 h, and fixed nuclei stained with propidium iodide were analyzed by flow cytometry. As shown in Figure 2
, resveratrol treatment of 32Dp210 cells increased the hypodiploid cells in sub-G1 phase in a time-related manner. At 72 h, 77% of the treated cells were in sub-G1 phase.
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, lanes 2, 3 and 4). No such ladder pattern was seen in untreated cells (lane 1). Resveratrol-induced DNA fragmentation in 32Dp210 cells was also analyzed by examination of the cytoplasmic histone-associated DNA fragments (mono- and oligonucleosomes) using a Cell Death Detection ELISA kit. Compared with untreated control cells, resveratrol treated cells exhibited 1- to 4-fold increases in internucleosomal DNA fragmentation at 50–200 µmol/L resveratrol (Fig. 3
B), corroborating DNA fragmentation seen in treated cells by gel electrophoresis. Because caspase-3 is a key protease associated with the fragmentation, the processing of caspase-3 in 32Dp210 cells treated with resveratrol was examined. For this purpose, we measured the proteolytic cleavage of DEVD-pNA by cell lysate prepared from cells treated with resveratrol. Resveratrol-treated cells showed marked increase in DVED-pNA cleavage (57%, 77% and 84% increases) after 16 h treatment with resveratrol at 25, 50, and 100 µmol/L (Fig. 4
).
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The in vitro inhibition of clonal expansion and the induction of apoptosis in 32Dp210 cells by resveratrol suggest that 32Dp210 cells treated in vitro with resveratrol may not progress to produce leukemia in vivo. To examine this, the development of leukemia and survival of mice injected with untreated and resveratrol-treated 32Dp210 cells was compared. For this purpose, 32Dp210 cells were treated with resveratrol at 100 µmol/L for 16 h. Treated or untreated cells (2.5 x 103) were injected intravenously into each mouse. As shown in Figure 5
A, all mice (100%; n = 9) injected with untreated 32Dp210 cells developed leukemia and died within 17 d (range: 13–17 d) with a mean survival time of 14.4 ± 1.4 d. In marked contrast (P < 0.001), only 1 of 13 mice injected with resveratrol-treated 32Dp210 cells died on d 19. All other mice (92%) were alive on d 60 after implantation of leukemia cells. To examine whether these survivors were free of leukemia, DNA isolated from the bone marrow cells obtained from surviving mice or that from a mouse injected with untreated 32Dp210 cells was analyzed for BCR/ABL by PCR. Only the bone marrow of the mouse injected with untreated 32Dp210 cells showed the presence of a 325-bp amplified fragment of the BCR/ABL gene (Fig. 5
B, lane 2). All of the bone marrow specimens from surviving mice tested negative for BCR/ABL (lanes 3–9), indicating that these mice were molecularly free of leukemia.
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The lack of leukemia development by 32Dp210 cells treated with resveratrol in vitro prompted us to examine whether this compound exerts antileukemic effects in vivo. In the first set of experiments, resveratrol was administered orally at a dose of 8 mg/kg once a day, 5 d per week, through out the experiment. This dose of resveratrol has been used previously in models of myocardial and chemical carcinogenesis protection studies by other investigators (20
,25
). Two groups of mice (eight mice in each group) were injected with 2.5 x 103 32Dp210 cells and mice in one group were treated with resveratrol as described. Mice were followed for survival to determine the antileukemic effect of resveratrol. All mice in the untreated control group as well those treated with resveratrol died with mean survival times of 14.3 ± 2.3 and 14.4 ± 2.0 d, respectively (Fig. 6A
), indicating lack of antileukemic effect in vivo at 8 mg/kg resveratrol against an inoculum of 2.5 x 103 32Dp210 cells (P = 0.888).
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B) with a mean survival time of 17.2 ± 3.9 d. All mice (100%) treated with 8 mg (n = 9) or 40 mg (n = 8) resveratrol/kg body weight also died with mean survival times of 19.0 ± 3.4 and 15.6 ± 4.1 d, respectively. Twelve of the 14 mice (86%) treated with 80 mg/kg body weight resveratrol also died between 14 and 36 d. The overall log rank test for these four groups was not significant (P = 0.103), nor was the test comparing the 80 mg/kg dose group to the controls. Two mice that survived in the 80-mg/kg dose group were tested for BCR/ABL oncogene on d 60 by PCR. Bone marrow, liver and spleen specimens of these mice were negative for BCR/ABL (data not shown), suggesting that these mice were free of leukemia. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,29
). The beneficial effects of red wine against these diseases have been attributed to resveratrol, a polyphenolic compound present in wine (29
). In the plant kingdom, especially in grapes, resveratrol is believed to provide protection against environmental stress and plant pathogens (30
). Numerous biological effects of resveratol, including anti-inflammatory, antiproliferative, and chemopreventive activities have been described. We have previously reported that resveratrol inhibits most of the T cell-mediated immune responses in vitro (28
) and selectively inhibits the clonogenic growth of several human and murine leukemia cell lines but not normal hematopoietic progenitor cells (27
). In this study, the antileukemic effect of resveratrol against 32Dp210 mouse myeloid leukemic cell in vitro and in vivo was investigated. These studies demonstrated that resveratrol inhibits the clonal growth of 32Dp210 cells in a dose-related manner with an IC50 of 23 µmol/L. A concentration of 25 µmol/L and above was highly inhibitory of clonal growth of 32Dp210 leukemia cells. The antiproliferative effect of resveratrol on these leukemia cells is irreversible, because cells do not resume growth after the removal of resveratrol from the cultures. The inhibition of the proliferation of 32Dp210 cells by resveratrol corroborates its previously reported antiproliferative effects against several other tumor cell lines (21
–24
). The inhibition of ribonucleotide reductase and DNA polymerase activation by resveratrol, two key enzymes involved in DNA synthesis (31
,32
), as well as suppression of the cell cycle traverse (33
) previously shown by other investigators, may account for the inhibition of the proliferation of 32Dp210 cells.
The irreversible inhibition of the growth of leukemia cells by resveratrol could result from triggering of the apoptotic cell death program in treated cells. In fact, FACS analysis revealed that treatment of 32Dp210 cells with resveratrol at a concentration of 50 µmol/L decreased the diploid cells with a corresponding increase in the hypodiploid (sub-G1) population in a time-dependent manner, suggesting that cytotoxicity induced by resveratrol is mediated by the induction of apoptosis. The observation that resveratrol induces apoptosis in 32Dp210 cells was further supported by the induction of internucleosomal DNA fragmentation and the cleavage of procaspase-3 in resveratrol treated cells. These results support the previously reported apoptosis-inducing activity of resveratrol against tumor cell lines (23
,34
). Various pathways of the apoptotic cell death program, including direct caspase-2 and caspase-6 activation (35
), up-regulation of p-53 and p-21 (36
), activation of Fas/Fas ligand pathway (34
), and even direct cleavage of DNA by resveratrol (37
) have been proposed for apoptotic cell death induced by resveratrol. In addition, resveratrol was shown to induce apoptosis in leukemia cell lines via a mitochondrial pathway controlled by Bcl-2, an antiapoptotic protein associated with the mitochondrial membrane (38
). Although the results of these studies clearly demonstrated induction of apoptosis by resveratrol in 32Dp210 cells, the exact pathway of the apoptotic cell death program induced by resveratrol in these cells remains to be established.
Resveratrol inhibits the proliferation of tumor cells lines (21
–24
) in vitro and provides protection against chemical carcinogenesis (20
,39
). In contrast, very little is known about the antitumor effect of resveratrol in vivo. In a few studies in which in vivo antitumor and antimetastatic activities of resveratrol were tested, only solid tumor implants were used. For example, reveratrol partially inhibited the tumor growth and metastasis of Lewis lung carcinoma and T241 fibrosarcoma in mice (40
,41
). The strong antiproliferative and proapoptotic effects of resveratrol against 32Dp210 leukemia cells in vitro led to the testing of antileukemic effects in vivo. In the initial experiment, mice were inoculated with 2.5 x 103 32Dp210 cells and treated them daily with a dose of 8 mg/kg body weight resveratrol orally. We inoculated mice with 2.5 x 103 leukemia cells because we have standardized this dose of 32Dp210 cells with respect to leukemia progression, spread of leukemia to various organs, and the survival time of inoculated mice (42
). Resveratrol at 8 mg/kg body weight was chosen because this dose results in a plasma concentration of resveratrol which can be achieved by daily consumption of three glasses of red wine, sufficient for cardioprotective effects. No antileukemic activity of resveratrol was observed at this dose. Even when the size of the leukemia cell inoculum was reduced and the dose of resveratrol was increased 10-fold, resveratrol doses of 8 mg/kg or 40 mg/kg body weight (4-fold higher) were ineffective in slowing down the progression of leukemia. At a dose of 80 mg/kg body weight (9-fold higher), resveratrol protected only a small fraction of mice from leukemia-induced death. These findings suggest that resveratrol, despite its antileukemic effects in vitro, is not very effective in preventing the progression of leukemia in vivo. Whether the antileukemic effect of resveratrol can be increased by administering even higher doses without toxicity or by administering it via other routes remains to be investigated. In summary, we have provided evidence that although resveratrol exhibits strong antiproliferative and proapoptotic activities against 32Dp210 murine myeloid leukemia cells in vitro, only at a very high dose does it partially protect mice against leukemia in vivo.
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FOOTNOTES |
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3 Abbreviation used: PCR, polymerase chain reaction.
Manuscript received 14 January 2002. Initial review completed 22 March 2002. Revision accepted 10 April 2002.
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