Cancer Research Grants Advances in Breast Cancer Research
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
[Cancer Research 59, 2596-2601, June 1, 1999]
© 1999 American Association for Cancer Research
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hsieh, T.-c.
Right arrow Articles by Wu, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hsieh, T.-c.
Right arrow Articles by Wu, J. M.
[Cancer Research 59, 2596-2601, June 1, 1999]
© 1999 American Association for Cancer Research

Carcinogenesis

Resveratrol Increases Nitric Oxide Synthase, Induces Accumulation of p53 and p21WAF1/CIP1, and Suppresses Cultured Bovine Pulmonary Artery EndothelialCell Proliferation by Perturbing Progression through S and G21

Tze-chen Hsieh, Gloria Juan, Zbigniew Darzynkiewicz and Joseph M. Wu2

Department of Biochemistry and Molecular Biology [T-c. H., J. M. W.] and Brander Cancer Research Institute [G. J., Z. D.], New York Medical College, Valhalla, New York 10595


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Epidemiological studies have shown that the regular consumption of red wine may in part account for the apparent compatibility of a high fat diet with a low incidence of coronary atherosclerosis. This phenomenon, commonly referred to as the French paradox, may be associated with red wine constituents that exhibit tumor-preventive properties as well as inhibit reactions that increase the risk of coronary heart disease. Here we show that resveratrol, a polyphenol in red wine, induces nitric oxide synthase, the enzyme responsible for the biosynthesis of NO, in cultured pulmonary artery endothelial cells, suggesting that resveratrol could afford cardioprotection by affecting the expression of nitric oxide synthase. We also show that resveratrol inhibits the proliferation of pulmonary artery endothelial cells, which, based on flow cytometric analysis, correlates with the suppression of cell progression through S and G2 phases of the cell cycle. Western blot analysis and immunocytochemical protein detection combined with multiparameter flow cytometry further demonstrate that the perturbed progression through S and G2 phases is accompanied by an increase in the expression of tumor suppressor gene protein p53 and elevation of the level of cyclin-dependent kinase inhibitor p21WAF1/CIP1. All of the observed effects of resveratrol, including induction of apoptosis at its higher concentration, are also compatible with its putative chemopreventive and/or antitumor activity.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Resveratrol (3,5,4'-trihydroxystibene) is a phytoalexin present in plants and various human foods (1) . A primary impetus for research on resveratrol has come from the paradoxical observation that a low incidence of CHD3 may coexist with intake of a high fat diet, a phenomenon known as the French paradox. Because of the French population’s preference for red wine, it has been suggested that red wine ingredients, including polyphenolic compounds such as resveratrol, may contribute to the observed congruence of the "French paradox" (1 , 2) . The exact mechanism by which resveratrol acts to mitigate a high fat diet from increasing the risk for CHD has not been totally elucidated but may relate to its ability to inhibit copper ion-catalyzed oxidation of low-density lipoprotein (3 , 4) , ribonucleotide reductase (5) , DNA polymerase (6) , suppressor of cell growth in general (7 , 8) , and other as yet undiscovered functions. Jang et al. (9) reported recently, using model assay systems, that resveratrol acts as a pleiotropic biological effector to regulate initiation, promotion, and progression that underlie malignant transformation. These studies add a new dimension to the expanding role of resveratrol as a potential cancer chemopreventive agent, because it possesses the three basic mechanisms envisaged for such agents, i.e., suppression of cell replication, induction of apoptosis, and restoration of differentiation (or reverse or abnormal differentiation; Ref. 10 ).

NO is a signal-transducing molecule discovered originally on the basis of its vasodilatory properties (11) . It is synthesized by NOS, which has three distinguishable isoforms, NOS-1 (ncNOS), NOS-2, and NOS-3 (ecNOS; Refs. 12 and 13 ). The last form, constitutively expressed in endothelial cells, may inhibit contractile tone and vascular smooth muscle cell proliferation through paracrinally produced NO (14) . Other biological functions ascribed to NO include inhibition of platelet adhesion and aggregation (15, 16, 17) , reduction of expression of adhesion molecule and chemokines (18, 19, 20, 21) , and suppression of cell growth and migration (22 , 23) . These emerging roles of NO play an integral part in the prevention of initiation, progression, and complications of atherosclerosis (23, 24, 25) For example, impairment of NO synthesis, or increased inactivation of NO by superoxide radicals, may account for the increased peripheral vascular tone associated with hypertension and may contribute to its clinical consequence (26) . Inhibition of NO production in bovine endothelial cells by an L-arginine antagonist reportedly induced DNA replication, promoted cellular transition from prereplicative to replicative phases, and increased c-myc and c-fos oncogene expression (27) .

Endothelial cells are known to play an integral role in maintaining the integrity and functioning of the vascular endothelium. Homeostasis of the vascular endothelium, both in terms of metabolic and physiological activities, is subject to fine tuning by individual nutrients or nutrient derivatives. We therefore investigated the effects of resveratrol on growth and specific gene expression of cultured BPAE cells. We found that resveratrol induced NOS, reduced endothelial cell proliferation, and most interestingly, perturbed progression through the cell cycle, particularly through late S and G2. Furthermore, the suppression of cell cycle progression upon treatment with resveratrol was accompanied by the accumulation of the tumor suppressor p53 concomitant with the cyclin-dependent kinases inhibitor p21WAF1/CIP1.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Stock solution (12.5 mM) of resveratrol (Sigma Chemical Co.) was prepared in DMSO and stored at -20°C. For treatment, the resveratrol was diluted in RPMI 1640 and added to cultures to give the desired final concentrations. Untreated cultures received the same amount of the carrier solvent (0.2% DMSO).

Cell Culture and Treatment with Resveratrol.
The BPAE cells isolated from the distal main intrapulmonary artery of calf lungs were generously provided by Dr. Susan C. Olson of this department. Relative homogeneity of the cell preparation and their identification as endothelial cells by fluorescent staining for diacylated low-density lipoprotein were based on procedures detailed in an earlier publication (28) . Cells were routinely maintained in MEM supplemented with 15% fetal bovine serum and containing D-valine instead of L-valine to suppress fibroblast growth, as described (28 , 29) . Cells seeded at an initial density of 1 x 105 cells/ml were treated with 10, 50, and 100 x 10-6 M resveratrol and maintained for up to 3 days. Cells were harvested by trypsinization, and the cell numbers were determined using a hemocytometer. Cell viability was checked by trypan blue exclusion.

Measurement of Cell Cycle Progression.
The effects of resveratrol on cell progression through the cell cycle were determined as described previously (30, 31, 32, 33, 34) .

Immunocytochemical Detection of p53.
The cells were harvested, washed with PBS, and fixed in suspension in ice-cold 80% ethanol for up to 24 h. After fixation, the cells were washed twice with PBS and then suspended in 1 ml of 0.25% Triton X-100 in PBS on ice for 5 min. The cells were then centrifuged (300 x g for 5 min); the cell pellet was suspended in 100 µl of PBS containing 0.5 µg of the FITC-conjugated anti-p53 monoclonal antibody (clone DO-7; PharMingen, San Diego, CA) and 1% BSA and incubated for 2 h at room temperature. Parallel cell samples were incubated with anti-p21WAF1/CIP1 monoclonal antibody (clone SX118; PharMingen), rinsed with PBS containing 1% BSA, and incubated with FITC-conjugated goat anti-mouse IgG antibody (Molecular Probes, Eugene, OR), as described (30, 31, 32, 33, 34) . The cells were then rinsed with PBS containing 1% BSA and resuspended in 5 µg/ml of propidium iodide (Molecular Probes) and 0.1% RNase A (Sigma) in PBS and incubated at room temperature for 20 min before measurement. Control cells were treated identically, except instead of using anti-p53 antibody, the cells were incubated with the isotypic antibody (IgG2b), at the same titer.

Cellular fluorescence was measured with the ELITE ESP flow cytometer/cell sorter (Coulter, Miami, FL) using the argon ion laser (emission at 488 nm). Fluorescence signals were collected using the standard configuration of the flow cytometer (green fluorescence for p53 and red fluorescence for propidium iodide); details of this analysis are presented elsewhere (30, 31, 32, 33, 34) .

Western Blot Analysis.
Control and treated cells were lysed by repeated freeze-thaw cycles with buffer containing 10 mM HEPES (pH 7.5), 90 mM KCl, 1.5 mM Mg(OAc)2, 1 mM DTT, 0.5% NP40, 5% glycerol, 0.5 mM phenylmethylsulfonyl fluoride, and 10 µg/ml each of the protease inhibitors aprotinin, pepstatin, and leupeptin. Cell-free extracts were obtained by centrifugation in a microcentrifuge. Lysates (7–10 µg) from control and treated cells were separated on 10% SDS-PAGE. The separated proteins were transferred to nitrocellulose membranes, and the membranes were incubated with the respective primary and secondary antibodies. Specific immunoreactive bands were identified by enhanced chemiluminescence or color reaction, as described previously (35, 36, 37) .


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Induction of ecNOS by Resveratrol.
Existence of the "French paradox" (1) , as well as the large body of epidemiological data pointing to protection by fruits and vegetables against CHD (38) , suggest that resveratrol could exert cardiovascular protective functions by effecting specific gene changes in endothelial cells, including those integrally involved in the biogenesis of NO. Because NO is a short-lived gas and virtually impossible to visualize directly, we tested the effects of resveratrol by assaying changes in ecNOS, an isoform of NOS specifically and constitutively expressed in endothelial cells. Western blot analysis showed that treatment of subconfluent BPAE cells with 50–100 µM resveratrol resulted in a 3-fold increase in ecNOS, whereas 10 µM resveratrol had no effect (Fig. 1)Citation .



View larger version (57K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Effects of resveratrol on expression of ecNOS. Cell extracts from control and day 3 resveratrol-treated cells were electrophoresed using 10% SDS PAGE. The detection of ecNOS, and reprobing of the blots for actin, by Western blot analysis, was as described in "Materials and Methods." The blots were scanned, and the intensity of the bands corresponding to the proteins being assayed was quantified and expressed as normalized arbitrary units. The data were averaged from two separate experiments, each assayed in triplicate.

 
Effects of Resveratrol on Growth of BPAE Cells.
To test whether resveratrol affected the growth of BPAE cells, asynchronous cells were incubated with various amounts of resveratrol, and the change in cell number over time was determined. Resveratrol inhibited cell proliferation in a time- and concentration-dependent manner, with 10 µM reducing growth by 30%, and 50–100 µM completely preventing cell proliferation after a 3-day treatment with the polyphenol (Fig. 2)Citation . When examined by phase contrast microscopy, control cells displayed the characteristic cobblestone-like growth patterns typical of these cells maintained in culture (28 , 29) . In contrast, cells treated with 50–100 µM resveratrol assumed a long, spindle-shaped morphology in the tissue culture flasks, which, following trypsinization and resuspension in PBS, appeared under the microscope predominately as giant cells, compared with the controls (data not shown).



View larger version (33K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Effects of resveratrol on growth of BPAE cells. Cell growth and viability, using cells treated with various concentrations of resveratrol for 72 h, was measured as described in "Materials and Methods." Values are the means of two experiments, each assayed in triplicate, with a SE (bars) of 15%.

 
Cell Cycle Effects of Resveratrol.
Exponentially growing untreated and resveratrol-treated BPAE cells were subjected to flow cytometric analysis after staining their DNA and immunocytochemical detection of either p53 or p21WAF1/CIP1 (Fig. 3)Citation . The DNA content frequency histograms (Fig. 3Citation , insets) clearly indicate that in the presence of resveratrol the cells accumulate in S and G2-M phases of the cycle. An increase in proportion of S phase cells, from 8 to 14% and of G2 cells from 4 to 9% was observed at 10 µM concentration of resveratrol.



View larger version (39K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 3. Effect of different concentrations of resveratrol on cell cycle and expression of p53 and p21WAF1/CIP1 of BPAE cells, measured by flow cytometry. Cells were treated with resveratrol for 72 h, and cycle analysis was measured in two separate experiments, with similar results. The scatterplots represent bivariate distributions of DNA content versus p53 (top panels) or DNA versus p21WAF1/CIP1 (bottom). The cells were untreated (A, control) or treated with 10, 50, and 100 µM resveratrol (B, C, and D, respectively) for 72 h. The insets represent cellular DNA content frequency histograms that reveal the cell cycle distribution in the respective cultures. On the basis of DNA content, one can distinguish cells in G1 from S and G2-M, as shown. Note accumulation of cells in the late portion of S phase (and also in G2-M) at 50 µM and at the very early portion of S at 100 µM concentration of resveratrol. Apoptotic cells (Ap) can be identified on the basis of their fractional DNA content.

 
A much more dramatic effect was evident at 50 µM concentration, where the proportion of S phase was increased to 35% and of G2 to 42%, concomitant with a drop in proportion of G1 cells from 82%, in control to 16% (Fig. 3A)Citation . Few cells altogether were present in the cultures treated with 100 µM resveratrol, but there was predominance of S and G2 cells in this culture as well (Fig. 3D)Citation . It is evident from the DNA content frequency histogram as well as from the p53 versus DNA, or p21 versus DNA scatterplots representing these cultures, that most cells were arrested in the late portion of the S phase. That is, the proportion of cells with DNA index 1.4–1.9 was about 4-fold greater than of the cells with DNA index between 1.1 and 1.3.

The presence of cells with fractional DNA content, which is a characteristic feature of apoptosis (39) , was also apparent in the resveratrol-treated cultures. Their frequency was increasing with the increase in concentration of resveratrol, from about 2% in control to 4, 7, and 20% at 10, 50, and 100 µM resveratrol, respectively.

Effect of Resveratrol on p53 and p21WAF1/CIP1 Expression.
Expression of p53, detected immunocytochemically, was increased in BPAE cells grown in the presence of resveratrol (Figs. 3Citation and 4Citation ). Minor increase, by ~50%, and only in G2-M cells, was observed at 10 µM resveratrol concentration. The increase, particularly for S and G2-M cells, was more pronounced at 50 and 100 µM resveratrol concentration (Figs. 3Citation and 4Citation ). Thus, at 50 µM concentration, whereas p53 level in G1 cells increased by 75%, it nearly quadrupled in S and G2-M cells. A similar trend was apparent at 100 µM concentration. Interestingly, the expression of p53 was greatly elevated in some cells with fractional DNA content.



View larger version (34K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 4. Resveratrol-induced changes in cell cycle distribution (A) and expression of p53 (B) and p21WAF1/CIP1 (C) of BPAE cells treated for 3 days with different concentrations of resveratrol (0–100 µM). The raw data, shown in Fig. 3Citation , were transformed, using the DNA histograms deconvolution program to estimate the percentage of apoptotic cells (Ap) and cells in G1, S and G2-M phases of the cycle (A). The mean values of p53-associated (B) or p21WAF1/CIP1-associated (C) immmunofluorescence were estimated separately for cells in G1, S, and G2-M phases of the cycle by gating analysis. These means were then corrected for the component of nonspecific fluorescence, by subtraction of the mean value of the cells stained with isotypic IgG, and normalized to be comparable with the mean value of G1 cell population of the cells from the untreated culture (= 100).

 
The resveratrol-induced increase in expression of p53 in BPAE cells was paralleled by the elevated level of p21WAF1/CIP1 (Figs. 3Citation and 4Citation ). As in the case of p53, the rise in p21WAF1/CIP1, when presented in the mean values (Fig. 4)Citation , was minimal at 10 µM concentration. However, because of intercellular variability in expression of p21WAF1/CIP1, even in the absence of significant changes in the mean value (Fig. 4)Citation , individual cells showed an elevated level of this protein at 10 µM resveratrol concentration (Fig. 3)Citation . The effect was much more pronounced at 50 and 100 µM resveratrol concentration and was observed at all phases of the cell cycle (Figs. 3Citation and 4Citation ).

Analysis of p53 levels by Western blotting confirmed findings by flow cytometry (Fig. 5)Citation . Thus, the expression of p53 was up-regulated in a dose-dependent manner, with 50–100 µM resveratrol resulting in a 60 and 72% increase, respectively, of p53. Expression of actin, however, was unaffected and remained comparable with control. Attempts to detect changes in the expression of p21WAF1/CIP1 by Western blot analysis, using two commercial antibodies (clones 18A10-H5-63.1 and SX118; PharMingen), failed to detect the presence of immunoreactive bands.



View larger version (70K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 5. Effects of resveratrol on expression of p53. Conditions of treatment and Western blot analyses were performed as described in the legend to Fig. 1Citation .

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present study was designed to test whether resveratrol, as a polyphenol present relatively abundantly in red wine, may exert cardioprotective effects and, as such, provide part of the mechanism underlying the French paradox. Because endothelial injury is commonly considered by many as playing a pivotal role in initiating atherosclerosis (40) , which accounts for the majority of newly diagnosed CHD cases (40 , 41) , we focused on studying the effects of resveratrol in BPAE. Our data show that the growth of BPAE cells in the presence of resveratrol led to several cellular changes, notably the induction of ecNOS, p53, and p21WAF1/CIP1 and suppression of cell proliferation. These data not only provide evidence supporting the hypothesis that resveratrol regulates endothelial cell growth but also for the first time indicate a role for the induction of ecNOS and p53 expression by this polyphenol. It is difficult to assess, at present, to what extent the induction of ecNOS is interrelated to the other changes. It is quite likely, however (as it will be discussed later), that inhibition of cell proliferation is causally associated with the observed up-regulation of p53 and induction of p21WAF1/CIP1. Taken together, these results give credence to the notion that resveratrol, through overexpression of ecNOS and p53, may reduce damage to the vascular endothelium and, in turn, the development of disease states such as atherosclerosis and thrombosis.

Regulation of Endothelial Cell Growth and ecNOS by Resveratrol.
The ability of resveratrol to modulate endothelial cell proliferation and specific gene expression changes may be significant in several ways. The endothelium, with its endothelial cell lining, presents an extremely critical and vulnerable site for oxidant injury, the results of which are losses of both microvascular metabolic function and barrier properties (25) . Vascular injury, due to excess production of reactive oxygen species, is known to occur secondary to diverse phenomena that include trauma, acute inflammation, sepsis, tissue ischemia-reperfusion, oxygen toxicity, and exposure to xenobiotics capable of redox recycling (25) . To minimize development of oxidant stress, the endothelial cells rely upon the presence of multiple overlapping defense mechanisms within its cellular milieu, including NO, that collectively serve to protect intracellular sites at risk from oxidant stress, including inhibition of the formation of reactive oxygen intermediates (25 , 42) . Our studies show that resveratrol, at concentrations comparable with those found in wines and grapes (1 , 9) , effectively suppresses endothelial cell proliferation and induces ecNOS (Fig. 1)Citation . Suppression of cell growth accompanied by their accumulation in the S and G2 phases of the cell cycle (Figs. 3Citation and 4Citation ) increases the likelihood that any damage, episodic or pervasive, sustained by the endothelial cells could be repaired in an orderly and timely fashion. The cumulative effect of such an inhibition could be decreased propensity for development of endothelial injury, which is often regarded as the triggering event for development of both the fatty streaks and the formation of atherosclerotic plaques (40 , 41) . Another implication of these findings is that resveratrol, taken in food or beverages, could provide a gradual yet sustained increase in NO production. The NO concentrations reached may be sufficient to tip the balance between prooxidant and antioxidant states, favoring the latter and providing an additional safeguard against endothelial cell damage.

Effect of Resveratrol on Cell Cycle Progression and Expression of p53 and p21WAF1/CIP1.
As revealed by flow cytometry, the cells accumulated in S and G2-M phase of the cycle. Because there was no evidence of the increased percentage of mitotic cells in the resveratrol-treated cultures, when examined by microscopy, the observed accumulation in G2-M indicates cell arrest in G2 rather than in mitosis. At higher resveratrol concentration and longer exposure times, apoptosis was detected; the apoptotic cells were characterized by fractional DNA content (Fig. 3)Citation .

It is plausible that the observed cell cycle effects induced by resveratrol were causally related to the up-regulation of p53 and p21WAF1/CIP1. That is, the present findings, using a combination of flow cytometry and Western blot analysis, demonstrated that the slowdown in cell progression through the cycle, which manifested in accumulation of cells in S and G2 phases of the cell cycle, was closely paralleled by the elevated levels of p53 and p21WAF1/CIP1. Thus, the cell arrest in S and G2-M, the increase in p53 and in p21WAF1/CIP1, all were observed at 50 and 100 µM resveratrol concentrations. However, although the absolute increase in p53 was most pronounced for cells in S and G2-M phase (Fig. 3)Citation , the increase was of similar magnitude when recalculated per unit of DNA, regardless of the cell cycle position (Fig. 4B)Citation . The up-regulation of p53 is, most likely, responsible for transcriptional induction of p21WAF1/CIP1. The latter is the key inhibitor of the cell cycle progression machinery arresting the cells at check-points, including the G2 checkpoint (43) to allow for repair of the damage, primarily to DNA. Its up-regulation in BPAE cells by resveratrol, as seen presently, is in all probability directly responsible for inhibiting the cyclin-dependent kinase complexes operated by Cdk2 and Cdc2 (Cdk1), and thereby for suppression of cell transit through S and G2.

Wild-type p53 is up-regulated in the cell by its increased half-life through inhibition of its degradation (44 , 45) , as well as modulation of its stability by posttranslational events such as phosphorylation and acetylation (46, 47, 48, 49, 50) . It is likely, therefore, that its up-regulation in BPAE cells by resveratrol occurs by similar types of mechanism. The role of p53, in addition to induction of p21WAF1/CIP1, is also in protection of the genome integrity via physical interaction with DNA, as well as in regulation of cell propensity to apoptosis. The latter function was shown to involve the induction of expression of the apoptosis-promoting gene bax (51) . High level of p53 expression in the cells with fractional DNA content (Fig. 3, C and D)Citation , i.e., in apoptotic cells, strongly suggests that their apoptosis may be associated with up-regulation of p53.

The resveratrol-induced suppression of BPAE cell proliferation, as observed presently in cultures, if it does occur in vivo, e.g., as a result of consumption of this agent, may have several consequences, that is, it is known that cell proliferation, in particular proliferation of vascular smooth muscle cells, plays the key role in pathogenesis of atherosclerosis (22, 23, 24, 25 , 40 , 41) . It is likely, therefore, that similar to BPAE, proliferation of vascular smooth muscle cells also is inhibited by resveratrol. If indeed resveratrol consumed as a constituent of red wine is responsible for lowering the incidence of atherosclerosis, this may be one of its possible mechanisms of action.

As mentioned in the "Introduction," there is evidence that resveratrol may have cancer chemopreventive activity. The effects of resveratrol on BPAE cells observed in the present study, i.e., induction of p53 and p21WAF1/CIP1, suppression of cell proliferation, cell cycle arrest at specific points in S and G2, and induction of apoptosis, all are compatible with its putative chemopreventive and/or antitumor activity.


   ACKNOWLEDGMENTS
 
We thank Dr. Susan C. Olson for supplying BPAE cells and for advice on maintaining the cells in culture. We extend special appreciation to Dr. Lisa Stein from PharMingen for providing antibodies against cyclins.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This research was supported in part by the Vivian Wu-Au Memorial Cancer Research Fund, by an unrestricted grant from the Philip Morris Co., Inc. (to J. M. W.), and by NIH National Cancer Institute Grant CA RO1 28 704 (to Z. D.). Back

2 To whom requests for reprints should be addressed, at Department of Biochemistry and Molecular Biology, Basic Sciences Building, Room 147, New York Medical College, Valhalla, NY 10595. Phone: (914) 594-4891; Fax: (914) 594-4058; E-mail: Joseph_Wu{at}nymc.edu Back

3 The abbreviations used are: CHD, coronary heart disease; NOS, NO synthase; ecNOS, NOS-3; BPAE, bovine pulmonary artery endothelial. Back

Received 1/ 7/99. Accepted 4/ 5/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Soleas G. J., Diamandis E. P., Goldberg D. M. Resveratrol. A molecule whose time has come? And gone?. Clin. Biochem., 30: 91-113, 1997.[Medline]
  2. Renaud S., DeLorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet, 339: 1523-1526, 1992.[Medline]
  3. Frankel E. N., Kanner J., German J. B., Parks E., Kinsella J. E. Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine. Lancet, 341: 454-457, 1993.[Medline]
  4. Kerry N. L., Abbey M. Red wine and fractionated phenolic compounds prepared from red wine inhibit low density lipoprotein oxidation in vitro. Atherosclerosis, 135: 93-102, 1997.[Medline]
  5. Fontecave M., Lepoivre M., Elleingand E., Gerez C., Guittet O. Resveratrol, a remarkable inhibitor of ribonucleotide reductase. FEBS Lett., 421: 277-279, 1998.[Medline]
  6. Sun N. J., Woo S. H., Cassady J. M., Snapka R. M. DNA polymerase and topoisomerase II inhibitors from Psoralea corylifolia. J. Nat. Prod., 61: 362-366, 1998.[Medline]
  7. Mgbonyebi O. P., Russo J., Russo I. H. Antiproliferative effect of synthetic resveratrol on human breast epithelial cells. Int. J. Oncol., 12: 865-869, 1998.[Medline]
  8. Della Ragione F., Cucciolla V., Borriello A., Della Pietra V., Racioppi L., Soldati G., Manna C., Galletti P., Zappia V. Resveratrol arrests the cell division cycle at S/G2 phase transition. Biochem. Biophys. Res. Commun., 250: 53-58, 1998.[Medline]
  9. Jang M., Cai L., Udeani G. O., Slowing K. V., Thomas C. F., Beecher C. W., Fong H. H., Farnsworth N. R., Kinghorn A. R., Mehta R. G., Moon R. C., Pezzuto J. M. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science (Washington DC), 275: 218-220, 1997.[Abstract/Free Full Text]
  10. Hong W. K., Sporn M. B. Recent advances in chemoprevention of cancer. Science (Washington DC), 278: 1073-1077, 1997.[Abstract/Free Full Text]
  11. Furchgott R. F., Zawadzki J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle cells by acetylcholine. Nature (Lond.), 288: 373-376, 1980.[Medline]
  12. Alexander B. The role of nitric oxide in hepatic metabolism. Nutrition, 14: 376-390, 1998.[Medline]
  13. Leonard N., Bishop A. E., Polak J. M., Talbot I. C. Expression of nitric oxide synthase in inflammatory bowel disease is not affected by corticosteroid treatment. J. Clin. Pathol., 51: 750-753, 1998.[Abstract]
  14. Balligand J. L., Cannon P. J. Nitric oxide synthases and cardiac muscle. Autocrine and paracrine influences. Arterioscler. Thromb. Vasc. Biol., 17: 1846-1858, 1997.[Abstract/Free Full Text]
  15. Radomski M. W., Palmer R. M. J., Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet, 2: 1057-1058, 1987.[Medline]
  16. Radomski M. W., Palmer R. M. J., Moncada S. The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. Biochem. Biophys. Res. Commun., 148: 1482-1489, 1987.[Medline]
  17. Radomski M. W., Palmer R. M., Moncada S. An L-arginine/nitric oxide pathway present in human platelet regulates aggregation. Proc. Natl. Acad. Sci. USA, 87: 5193-5197, 1987.[Abstract/Free Full Text]
  18. Bath P. M. W., Hassal D. G., Gladwin A. M., Palmer R. M., Martin J. F. Nitric oxide and prostacyclin: divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro. Arterioscler. Thromb., 11: 254-260, 1991.[Abstract/Free Full Text]
  19. Kubes P., Suzuki M., Granger D. N. Nitric oxide: an endogenous modulator of leucocyte adhesion. Proc. Natl. Acad. Sci. USA, 87: 4651-4655, 1991.
  20. Gauthier T. W., Scalia R., Murohara T., Guo J. P., Lefer A. M. Nitric oxide protects against leukocyte-endothelium interactions in the early stages of hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol., 15: 1652-1659, 1995.[Abstract/Free Full Text]
  21. Zeiher A. M., Fisslthaler B., Schray-Utz B., Busse R. Nitric oxide modulates the expression of monocyte chemoattractant protein in cultured human endothelial cells. Circ. Res., 76: 980-986, 1995.[Abstract/Free Full Text]
  22. Sarkar R., Meinberg E. G., Stanley J. C., Gordon D., Webb R. C. Nitric oxide reversibly inhibits the migration of cultured smooth muscle cells. Circ. Res., 78: 225-230, 1996.[Abstract/Free Full Text]
  23. Lloyd-Jones D. M., Bloch K. D. The vascular biology of nitric oxide and its role in atherogenesis. Annu. Rev. Med., 47: 365-375, 1996.[Medline]
  24. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J., 6: 3051-3064, 1992.[Abstract]
  25. Kuo P. C., Schroeder R. A. The emerging multifaceted roles of nitric oxide. Ann. Surg., 221: 220-235, 1995.[Medline]
  26. Ferro C. J., Webb D. J. Endothelial dysfunction and hypertension. Drugs, 53 (Suppl. 1): 30-41, 1997.
  27. Lopez-Farre A., Sanchez-de-Miguel L., Caramelo C., Gomez-Macias J., Garcia R., Mosquera J. R., deFrutos T., Millas I., Rivas F., Echezarreta G., Casado S. Role of nitric oxide in autocrine control of growth and apoptosis of endothelial cells. Am. J. Physiol., 272: H760-H768, 1997.[Abstract/Free Full Text]
  28. Olson S. C., Dowds T. A., Pino P. A., Barry M. T., Burke-Wolin T. ANG II stimulates endothelial nitric oxide synthase expression in bovine pulmonary artery endothelium. Am. J. Physiol., 273: L315-L321, 1997.[Abstract/Free Full Text]
  29. Picciano P. T., Johnson B., Walenga R. W., Donovan M., Borman B. J., Douglas W. H. J., Kreutzer D. L. Effects of D-valine on pulmonary artery endothelial cell morphology and function in cell culture. Exp. Cell. Res., 151: 134-147, 1984.[Medline]
  30. Darzynkiewicz Z., Gong J., Juan G., Ardelt B., Traganos F. Cytometry of Cyclin Proteins. Cytometry, 25: 1-13, 1996.[Medline]
  31. Juan G., Darzynkiewicz Z. Bivariate analysis of DNA content and expression of cyclin proteins Robinson J. P. eds. . Protocols in Cytometry, : 7-9, Wiley Liss New York 1997.
  32. Juan G., Darzynkiewicz Z. Detection of cyclins in individual cells by flow and laser scanning cytometry Jaroczeski M. J. Heller R. eds. . Methods in Molecular Biology, VXX: 1-9, Humana Press, Inc. Clifton, NJ 1997.
  33. Juan G., Li X., Darzynkiewicz Z. Correlation between DNA replication and expression of cyclins A and B1in individual MOLT-4 cells. Cancer Res., 57: 803-807, 1997.[Abstract/Free Full Text]
  34. Juan G., Traganos F., James W. M., Ray J. M., Roberge M., Sauve D. M., Anderson H., Darzynkiewicz Z. Histone H3 phosphorylation and expression of cyclins A and B1 measured in individual cells during their progression through G2 and mitosis. Cytometry, 32: 1-8, 1998.[Medline]
  35. Hsieh T. C., Wu J. M. Induction of apoptosis and altered nuclear/cytoplasmic distribution of the androgen receptor and prostate specific antigen by 1{alpha},25-dihydroxyvitamin D3 in androgen-responsive LNCaP cells. Biochem. Biophys. Res. Commun., 235: 539-544, 1997.[Medline]
  36. Hsieh T. C., Wu J. M. Differential expression and regulation of p53in human prostatic cells. Int. J. Oncol., 10: 1109-1112, 1997.
  37. Hsieh T. C., Wu J. M. Effects of fenretinide (4-HPR) on prostate LNCaP cell growth, apoptosis, and prostate-specific gene expression. Prostate, 33: 97-104, 1997.[Medline]
  38. Renaud S., DeLorgeril M. Nutrition, atherosclerosis and coronary heart disease. Reprod. Nutr. Dev., 34: 599-607, 1994.
  39. Darzynkiewicz Z., Juan G., Li X., Gorczyca W., Murakami T., Traganos F. Cytometry in cell necrobiology: analysis of apoptosis and accidental cell death (necrosis). Cytometry, 27: 1-20, 1997.[Medline]
  40. Ross R., Glomset J. A. The pathogenesis of atherosclerosis. N. Engl. J. Med., 295: 369-373, 1976.[Medline]
  41. Gutstein W. H., Wu J. M. Diana J. N. eds. . CNS and Atherosclerosis: Interrelationship in Smoking and Atherosclerosis, : 359-380, Plenum Publishing Corp. New York 1990.
  42. Chakraborti T., Ghosh S. K., Michael J. R., Batabyal S. K., Chakraborti S. Targets of oxidative stress in cardiovascular system. Mol. Cell. Biochem., 187: 1-10, 1998.[Medline]
  43. Bunz F., Dutriaux A., Lenguer C., Waldman T., Zhou S., Brown J. P., Sedivy J. M., Kinzler K. W., Vogelstein B. Requirement for p53 and p21 to sustain G2 arrest after DNSA damage. Science (Washington DC), 282: 1497-1501, 1998.[Abstract/Free Full Text]
  44. Furihata M., Sonobe H., Ohtsuki Y. The aberrant p53 gene. Int. J. Oncol., 6: 1209-1226, 1995.
  45. Harris C. C. Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies. J. Natl. Canc. Inst., 88: 1442-1455, 1996.[Abstract/Free Full Text]
  46. Takenaka I., Morin F., Seizinger B. R., Kley N. Regulation of the sequence-specific DNA sequence binding function of p53 by a protein kinase C and protein phosphatases. J. Biol. Chem., 270: 5405-5411, 1995.[Abstract/Free Full Text]
  47. Milne D. M., Campbell L. E., Campbell D. G., Meek D. W. p53 is phosphorylated in vitro and in vivo by an ultraviolet radiation-induced protein kinase characteristic of the c-Jun kinase, JNK1. J. Biol. Chem., 270: 5511-5518, 1995.[Abstract/Free Full Text]
  48. Kapoor M., Lozano G. Functional activation of p53 via phosphorylation following DNA damage by UV but not gamma radiation. Proc. Natl. Acad. Sci. USA, 95: 2834-2837, 1998.[Abstract/Free Full Text]
  49. Chernov M. V., Ramana C. V., Adler V. V., Stark G. R. Stabilization and activation of p53 are regulated independently by different phosphorylation events. Proc. Natl. Acad. Sci. USA, 95: 2284-2289, 1998.[Abstract/Free Full Text]
  50. Sagakuchi K., Herrera J. E., Saito S., Miki T., Bustin M., Vassilev A., Anderson C. W., Appella E. DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev., 12: 2831-2841, 1998.[Abstract/Free Full Text]
  51. Miyashita T., Reed J. C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell, 80: 293-299, 1995.[Medline]



This article has been cited by other articles:


Home page
 J. Nutr.Home page
P. Gresele, P. Pignatelli, G. Guglielmini, R. Carnevale, A. M. Mezzasoma, A. Ghiselli, S. Momi, and F. Violi
Resveratrol, at Concentrations Attainable with Moderate Wine Consumption, Stimulates Human Platelet Nitric Oxide Production
J. Nutr., September 1, 2008; 138(9): 1602 - 1608.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
J. W. E. Rush, J. Quadrilatero, A. S. Levy, and R. J. Ford
Chronic Resveratrol Enhances Endothelium-Dependent Relaxation but Does Not Alter eNOS Levels in Aorta of Spontaneously Hypertensive Rats
Experimental Biology and Medicine, June 1, 2007; 232(6): 814 - 822.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. Ferrer, M. Asensi, S. Priego, M. Benlloch, S. Mena, A. Ortega, E. Obrador, J. M. Esteve, and J. M. Estrela
Nitric Oxide Mediates Natural Polyphenol-induced Bcl-2 Down-regulation and Activation of Cell Death in Metastatic B16 Melanoma
J. Biol. Chem., February 2, 2007; 282(5): 2880 - 2890.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
S. Das, A. Tosaki, D. Bagchi, N. Maulik, and D. K. Das
Potentiation of a Survival Signal in the Ischemic Heart by Resveratrol through p38 Mitogen-Activated Protein Kinase/Mitogen- and Stress-Activated Protein Kinase 1/cAMP Response Element-Binding Protein Signaling
J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 980 - 988.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
M. Sengottuvelan, P. Viswanathan, and N. Nalini
Chemopreventive effect of trans-resveratrol - a phytoalexin against colonic aberrant crypt foci and cell proliferation in 1,2-dimethylhydrazine induced colon carcinogenesis
Carcinogenesis, May 1, 2006; 27(5): 1038 - 1046.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
A. Kotha, M. Sekharam, L. Cilenti, K. Siddiquee, A. Khaled, A. S. Zervos, B. Carter, J. Turkson, and R. Jove
Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein.
Mol. Cancer Ther., March 1, 2006; 5(3): 621 - 629.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Interv.Home page
D. K. Das and N. Maulik
Resveratrol in cardioprotection: a therapeutic promise of alternative medicine.
Mol. Interv., February 1, 2006; 6(1): 36 - 47.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. M. Klinge, K. A. Blankenship, K. E. Risinger, S. Bhatnagar, E. L. Noisin, W. K. Sumanasekera, L. Zhao, D. M. Brey, and R. S. Keynton
Resveratrol and Estradiol Rapidly Activate MAPK Signaling through Estrogen Receptors {alpha} and {beta} in Endothelial Cells
J. Biol. Chem., March 4, 2005; 280(9): 7460 - 7468.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
S. B. Jones, S. E. DePrimo, M. L. Whitfield, and J. D. Brooks
Resveratrol-Induced Gene Expression Profiles in Human Prostate Cancer Cells
Cancer Epidemiol. Biomarkers Prev., March 1, 2005; 14(3): 596 - 604.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
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]

Home page
 Vasc MedHome page
S. M Wasserman and J. N Topper
Adaptation of the endothelium to fluid flow: in vitro analyses of gene expression and in vivo implications
Vascular Medicine, February 1, 2004; 9(1): 35 - 45.
[Abstract] [PDF]

Home page
 Cancer Res.Home page
A. W. Opipari Jr., L. Tan, A. E. Boitano, D. R. Sorenson, A. Aurora, and J. R. Liu
Resveratrol-induced Autophagocytosis in Ovarian Cancer Cells
Cancer Res., January 15, 2004; 64(2): 696 - 703.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
S. PERVAIZ
Resveratrol: from grapevines to mammalian biology
FASEB J, November 1, 2003; 17(14): 1975 - 1985.
[Full Text] [PDF]

Home page
 BloodHome page
Z. Estrov, S. Shishodia, S. Faderl, D. Harris, Q. Van, H. M. Kantarjian, M. Talpaz, and B. B. Aggarwal
Resveratrol blocks interleukin-1{beta}-induced activation of the nuclear transcription factor NF-{kappa}B, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells
Blood, August 1, 2003; 102(3): 987 - 995.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
F. Pellegatta, A. A. Bertelli, B. Staels, C. Duhem, A. Fulgenzi, and M. E. Ferrero
Different short- and long-term effects of resveratrol on nuclear factor-{kappa}B phosphorylation and nuclear appearance in human endothelial cells
Am. J. Clinical Nutrition, May 1, 2003; 77(5): 1220 - 1228.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
U. G. B. Haider, D. Sorescu, K. K. Griendling, A. M. Vollmar, and V. M. Dirsch
Resveratrol Increases Serine15-Phosphorylated but Transcriptionally Impaired p53 and Induces a Reversible DNA Replication Block in Serum-Activated Vascular Smooth Muscle Cells
Mol. Pharmacol., April 1, 2003; 63(4): 925 - 932.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
U. G. B. Haider, D. Sorescu, K. K. Griendling, A. M. Vollmar, and V. M. Dirsch
Resveratrol Suppresses Angiotensin II-Induced Akt/Protein Kinase B and p70 S6 Kinase Phosphorylation and Subsequent Hypertrophy in Rat Aortic Smooth Muscle Cells
Mol. Pharmacol., October 1, 2002; 62(4): 772 - 777.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Banerjee, C. Bueso-Ramos, and B. B. Aggarwal
Suppression of 7,12-Dimethylbenz(a)anthracene-induced Mammary Carcinogenesis in Rats by Resveratrol: Role of Nuclear Factor-{kappa}B, Cyclooxygenase 2, and Matrix Metalloprotease 9
Cancer Res., September 1, 2002; 62(17): 4945 - 4954.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
H. Ferry-Dumazet, O. Garnier, M. Mamani-Matsuda, J. Vercauteren, F. Belloc, C. Billiard, M. Dupouy, D. Thiolat, J. P. Kolb, G. Marit, et al.
Resveratrol inhibits the growth and induces the apoptosis of both normal and leukemic hematopoietic cells
Carcinogenesis, August 1, 2002; 23(8): 1327 - 1333.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
X. Gao, Y. X. Xu, G. Divine, N. Janakiraman, R. A. Chapman, and S. C. Gautam
Disparate In Vitro and In Vivo Antileukemic Effects of Resveratrol, a Natural Polyphenolic Compound Found in Grapes
J. Nutr., July 1, 2002; 132(7): 2076 - 2081.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
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]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. Shih, F. B. Davis, H.-Y. Lin, and P. J. Davis
Resveratrol Induces Apoptosis in Thyroid Cancer Cell Lines via a MAPK- and p53-Dependent Mechanism
J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1223 - 1232.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
F. Orallo, E. Alvarez, M. Camina, J. M. Leiro, E. Gomez, and P. Fernandez
The Possible Implication of trans-Resveratrol in the Cardioprotective Effects of Long-Term Moderate Wine Consumption
Mol. Pharmacol., February 1, 2002; 61(2): 294 - 302.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
F. Wolter, A. Clausnitzer, B. Akoglu, and J. Stein
Piceatannol, a Natural Analog of Resveratrol, Inhibits Progression through the S Phase of the Cell Cycle in Colorectal Cancer Cell Lines
J. Nutr., February 1, 2002; 132(2): 298 - 302.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
J. Gusman, H. Malonne, and G. Atassi
A reappraisal of the potential chemopreventive and chemotherapeutic properties of resveratrol
Carcinogenesis, August 1, 2001; 22(8): 1111 - 1117.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
K. P. L. Bhat and J. M. Pezzuto
Resveratrol Exhibits Cytostatic and Antiestrogenic Properties with Human Endometrial Adenocarcinoma (Ishikawa) Cells
Cancer Res., August 1, 2001; 61(16): 6137 - 6144.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
F. Wolter, B. Akoglu, A. Clausnitzer, and J. Stein
Downregulation of the Cyclin D1/Cdk4 Complex Occurs during Resveratrol-Induced Cell Cycle Arrest in Colon Cancer Cell Lines
J. Nutr., August 1, 2001; 131(8): 2197 - 2203.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
N. Ahmad, V. M. Adhami, F. Afaq, D. K. Feyes, and H. Mukhtar
Resveratrol Causes WAF-1/p21-mediated G1-phase Arrest of Cell Cycle and Induction of Apoptosis in Human Epidermoid Carcinoma A431 Cells
Clin. Cancer Res., May 1, 2001; 7(5): 1466 - 1473.
[Abstract] [Full Text]

Home page
 Cancer Res.Home page
Y.-P. Lu, Y.-R. Lou, X. H. Li, J. G. Xie, D. Brash, M.-T. Huang, and A. H. Conney
Stimulatory Effect of Oral Administration of Green Tea or Caffeine on Ultraviolet Light-induced Increases in Epidermal Wild-Type p53, p21(WAF1/CIP1), and Apoptotic Sunburn Cells in SKH-1 Mice
Cancer Res., September 1, 2000; 60(17): 4785 - 4791.
[Abstract] [Full Text]

Home page
 Cardiovasc ResHome page
B. Halliwell
Lipid peroxidation, antioxidants and cardiovascular disease: how should we move forward?
Cardiovasc Res, August 18, 2000; 47(3): 410 - 418.
[Full Text] [PDF]

Home page
 J. Immunol.Home page
S. K. Manna, A. Mukhopadhyay, and B. B. Aggarwal
Resveratrol Suppresses TNF-Induced Activation of Nuclear Transcription Factors NF-{kappa}B, Activator Protein-1, and Apoptosis: Potential Role of Reactive Oxygen Intermediates and Lipid Peroxidation
J. Immunol., June 15, 2000; 164(12): 6509 - 6519.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
P. F. Davies
Spatial Hemodynamics, the Endothelium, and Focal Atherogenesis : A Cell Cycle Link?
Circ. Res., February 4, 2000; 86(2): 114 - 116.
[Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. A. Stivala, M. Savio, F. Carafoli, P. Perucca, L. Bianchi, G. Maga, L. Forti, U. M. Pagnoni, A. Albini, E. Prosperi, et al.
Specific Structural Determinants Are Responsible for the Antioxidant Activity and the Cell Cycle Effects of Resveratrol
J. Biol. Chem., June 15, 2001; 276(25): 22586 - 22594.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
K. Lin, P.-P. Hsu, B. P. Chen, S. Yuan, S. Usami, J. Y.-J. Shyy, Y.-S. Li, and S. Chien
Molecular mechanism of endothelial growth arrest by laminar shear stress
PNAS, August 15, 2000; 97(17): 9385 - 9389.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
O. Holian, S. Wahid, M. J. Atten, and B. M. Attar
Inhibition of gastric cancer cell proliferation by resveratrol: role of nitric oxide
Am J Physiol Gastrointest Liver Physiol, May 1, 2002; 282(5): G809 - G816.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hsieh, T.-c.
Right arrow Articles by Wu, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hsieh, T.-c.
Right arrow Articles by Wu, J. M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online