Download Wine and resveratrol: mechanisms of cancer prevention?

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Wine and resveratrol: mechanisms of cancer prevention?
F Bianchini and H Vainio
Low alcohol consumption seems to decrease total mortality and to have beneficial properties on cardiovascular
disease; data for cancer are still inconclusive. There is
evidence that wine consumption decreases the risk of
cancer at several sites, including cancer of upper digestive
tract, lung, colon, basal cell carcinoma, and non-Hodgkin
lymphoma. The presence of resveratrol, a polyphenol
specifically present in red wine, may contribute to these
cancer preventive effects. Resveratrol in fact inhibits the
metabolic activation of carcinogens, has antioxidant and
anti-inflammatory properties, decreases cell proliferation
and induces apoptosis. Data on the availability of resveratrol in vivo are however still lacking. Although regular
consumption of one or two glasses of wine seems
reasonably safe from the health point of view, a recom-
Introduction
It has been estimated that 3% of all cancer deaths in the
USA can be attributed to alcohol consumption (Doll and
Peto, 1981). Alcoholic beverages have been classified as
carcinogenic to humans (Group 1) by the International
Agency for Research on Cancer (IARC, 1988). Alcohol
consumption is also known to be positively associated
with several other diseases, including cardiovascular
disease, stroke, gastric and duodenal ulcers, liver cirrhosis
and pancreatitis. However, evidence is accumulating that
drinking low to moderate amount of alcohol (1–2 drinks/
day) might also have beneficial effects.
In the present paper we briefly summarize, although not
exhaustively, most of the epidemiological literature on
possible cancer-preventive effects of moderate consumption of alcohol, and discuss possible responsible biological
mechanisms.
mendation to the general population for low wine consumption is not justified. European Journal of Cancer
c 2003 Lippincott Williams &
Prevention 12:417–425 Wilkins.
European Journal of Cancer Prevention 2003, 12:417–425
Key words: Alcohol, cancer prevention, resveratrol, wine
International Agency for Research on Cancer, Unit of Chemoprevention, 150
Cours Albert Thomas, 69372 Lyon Cedex 08, France.
Correspondence to: F Bianchini.
Fax: ( + 33) 4 72 73 83 19. E-mail: [email protected]
Received 27 March 2003 Accepted 6 June 2003
drinks per week; RR = 0.83) and moderate drinkers (5–
29.9 g alcohol per day, corresponding to 3–15 drinks per
week; RR = 0.88), mainly due to a decrease of deaths
from cardiovascular disease (Fuchs et al., 1995). A previous
follow-up had also shown that mortality from ischaemic
stroke was lowest when consuming 5–24.9 g alcohol per
day; in contrast, a strong increase of mortality from
haemorrhagic stroke was observed for the same consumption of alcohol (Stampfer et al., 1988). Low to moderate
consumption of alcohol also reduced the risk of ischaemic
stroke, angina and myocardial infarction in US male
physicians while no significant effect was observed for
haemorrhagic stroke (Camargo et al., 1997; Berger et al.,
1999; Mukamal et al., 2003). Several other studies have
demonstrated a negative association between moderate
alcohol consumption and coronary heart disease (Yano et
al., 1977; Boffetta and Garfinkel, 1990; Rimm et al., 1991).
Alcohol consumption and cancer risk
Total alcohol consumption and overall
mortality
The presence of a J-shaped relationship (i.e., the
relationship is not linear at low doses and the lower
value of relative risk (RR) does not correspond to the
lowest consumption) between alcohol consumption and
total mortality has been well documented. For example,
in a meta-analysis of 16 cohort studies the lowest
mortality for all causes was observed for men consuming
1–2 drinks per day and for women consuming less than
one drink per day (Holman et al., 1996). In the Nurses
Health Study in the USA, total mortality was lower in
light (1.5–4.9 g alcohol per day, corresponding to 1–3
c 2003 Lippincott Williams & Wilkins
0959-8278 Data on possible beneficial effects of moderate consumption of total alcohol on cancer development are less
convincing. In a cohort study among middle-aged
Japanese men the lowest risk of mortality from all causes
and from cancer was observed in those consuming 1–149 g
alcohol per week (1–2 drinks per day) (Tsugane et al.,
1999). The effect was significant only in non-smokers,
although the trend was similar for smokers. Nevertheless,
some meta-analyses have shown an increase of the risk of
breast and colon cancer with consumption of one and two
drinks per day, respectively (Longnecker et al., 1990;
Longnecker, 1994). Thus, a meta-analysis by Corrao
et al. (1999) showed that even 25 g alcohol per day
DOI: 10.1097/01.cej.0000090185.08740.59
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418 European Journal of Cancer Prevention 2003, Vol 12 No 5
(corresponding to about two drinks or two glasses of
wine), increased approximately two-fold the risk of
cancers of the upper aerodigestive tract and was associated
with a weaker but significant increase in colorectal and
breast cancers. This meta-analysis, however, was based on
a small number of studies due to strict inclusion criteria,
and there was a strong evidence of heterogeneity across
studies. A large prospective study of mortality among US
adults showed that even one drink per day increased the
risk of death for cancer of the upper aerodigestive tract
and liver in men, and cancer of the breast in women; no
effect was reported for colon in either gender (Thun et al.,
1997). In the Framingham Study, a follow-up of more than
40 years showed that consumption of alcohol up to 15 g
per day was not associated with an increase of breast
cancer risk (RR = 0.7, 95% C.I. = 0.5–1.1) (Zhang et al.,
1999). Finally, a pooled analysis of six prospective studies
with at least 200 incident breast cancer cases showed that
the risk increased linearly with increasing intake up to 60 g
alcohol per day (approximately four drinks), although the
increase in risk was not significant below 30 g alcohol per
day (Smith-Warner et al., 1998).
Differential effects by specific beverages
Differential effects of specific alcoholic beverages have
been hypothesized. Renaud et al. (1998) evaluated the
effect of alcohol consumption on mortality in a prospective study on 34 000 middle-aged men from eastern
France. The lowest total mortality (RR = 0.7), mortality
from cardiovascular disease (RR = 0.65) and mortality
from cancer (RR about 0.8) was observed for 22–32 g
alcohol per day. The proportional decrease in total
mortality was similar for smokers, non-smokers and exsmokers. As wine represented around 82% of alcohol
intake in this cohort, the observed effects were attributed
to wine consumption (2–5 drinks per day); however, only
a few subjects were exclusively wine drinkers, so that
possible protective effect of other alcoholic beverages
could not be excluded. Results provided so far are still
inconsistent and some meta-analysis and systematic
reviews have not supported a preferential effect of small
doses of wine compared with other alcoholic beverages in
the reduction of mortality from coronary heart disease
and myocardial infarction (Rimm et al., 1996; Cleophas,
1999; Mukamal et al., 2003).
A few cohort studies have analysed the preferential effect
of low intake of different beverages on cancer risk (Table
1). A pooled cohort study in Denmark reported that light
drinkers (8–21 drinks per week) had lower mortality from
all cause or from coronary heart disease, but no changes in
cancer risk (Grønbæk et al., 2000). When individual
beverages were considered, light consumption (8–21
drinks per week) of beer and spirit had no effect on
total mortality, decreased the risk of coronary heart
disease and slightly increased the risk of cancer; in
contrast, similar consumption of wine decreased not only
the mortality from coronary heart disease, but also
mortality from all causes and from cancer. When data
were stratified for wine drinkers and non-wine drinkers,
wine drinkers had a lower risk of death from coronary
heart disease and cancer at all levels of total alcohol
intake; however, the observed RR for wine drinkers was
always lower than one for coronary heart disease but
became higher than one for cancer when the daily
consumption was more than three drinks per day. In the
same-pooled cohort study the relative risk for specific
cancer sites was also estimated. The risk of lung cancer in
men was much decreased by consumption of over 13
drinks of wine per week (RR = 0.44), while consumption
of corresponding amounts of beer and spirits increased
the risk (Prescott et al., 1999). In the same cohort in
Denmark consumption of seven or more drinks of beer or
spirits per week significantly increased the risk of cancer
of the upper digestive tract, while the same consumption
of wine gave a relative risk of 0.4 (0.2–0.8) (Grønbæk et
al., 1998). Thus, when the proportion of wine in total
alcohol intake was over 30%, consumption of seven to 21
drinks per week was associated with a relative risk of 0.5
while subjects who drank the same amount of alcohol but
no wine had a relative risk of three.
A prospective study in Canada reported that 10–20 g
alcohol per day was associated with a slight increase in
mortality from breast cancer; this increase was mainly
limited to consumption of wine (Jain et al., 2000). No
major increase was observed with less than 10 g wine per
day (RR = 1.05). In the Framingham Study, in the USA,
the risk of breast cancer was not significantly associated
to consumption of wine, beer or spirit (Zhang et al., 1999).
The Pooling Project of Prospective Cohort Studies in the
USA reported approximately a 10% increase of breast
cancer risk by each daily increase of 10 g alcohol; the
effect of wine was not significant (RR = 1.05; CI, 0.98–
1.12), although similar to that of beer (RR = 1.11) and
spirits (RR = 1.05) (Smith-Warner et al., 1998). Consumption of red wine tends to decrease the risk of basal
cell carcinoma in women (P = 0.004), but not in men
(Fung et al., 2002), while consumption of spirits increased
the risk, although not significantly.
A possible, preferential effect of wine on cancer risk was
less evident when assessed in case-control studies (Table
2). Low consumption of wine (but not beer and/or spirits)
reduced by about 60% the risk of non-Hodgkin’s
lymphoma (Briggs et al., 2002), and by 40–50% the risk
of adenocarcinoma of the oesophagus and gastric cardia
(Gammon et al., 1997). However, several other studies did
not show any association between wine drinking and risk
of cancers of the endometrium, colorectum and adenocarcinoma of the oesophagus. Regarding breast cancer,
risk was increased in pre-menopausal women consuming
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Table 1
Cancer incidence and low alcohol consumption. Cohort studies
Endpoint
Study, country
Population
No of
cases
Alcohol intake
Relative riska ( ± 95%
confidence interval)
Reference
Grønbæk et al., 2000
Adjustment
Pooled cohort studies,
Denmark
Men and women aged 20–98
1552
8–21 drinks/week
0.78 (0.64–0.96) wine
1.32 (1.12–1.55) beer
1.13 (0.93–1.38) spirits
Incidence of lung cancer
Pooled cohort studies,
Denmark
Men and women aged Z 20
674
> 13 drinks/week
Wine:
Prescott et al., 1999
Men 0.44 (0.22–0.86)
Women 0.18 (0.03–1.33)
Beer:
Men 1.36 (1.02–1.82)
Women 1.49 (0.70–3.13)
Spirits:
Men 1.46 (0.99–2.14)
Women 0.67 (0.21–2.18)
Age, study cohort, smoking, education
Incidence of upper
aerodigestive tract
cancer
Pooled cohort studies,
Denmark
Men and women aged 20–98
156
Z 7 drinks/week
0.4 (0.2–0.8) wine
2.9 (1.8–4.8) beer
1.5 (1.2–1.9) spirits
Grønbæk et al., 1998
Age, study cohort, smoking, education
Death for breast cancer
National Breast Screening
Study, Canada
Women aged 40–59
223
0– r 10 g/day
1.05 (1.02–1.07) wine
1.04 (1.02–1.07) beer
0.97 (0.96–0.99) spirits
Jain et al., 2000
Age at enrolment, reproductive factors, family
history, smoking, education,
mammography,
breast self examination,
BMI, energy intake
Incidence of
breast cancer
Framingham Study, USA
Women aged 28–62
(original cohort) and
aged 12–60 (offspring
cohort)
287
1– < 3 drinks/week
0.7 (0.4–1.3) wine
1.0 (0.5–1.7) beer
0.7 (0.5–1.3) spirits
Zhang et al., 1999
Education, height, BMI,
physical activity, reproductive factors, smoking,
HRT, other alcoholic
beverages
Incidence of
breast cancer
Pooled analysis of
6 cohort studies, USA
Women aged 34–76
(total range)
4335
Daily increases of
10 g alcohol
1.05 (0.98–1.12) wine
1.11 (1.04–1.19) beer
1.05 (1.01–1.10) spirits
Smith-Warner et al., 1998 Not specified
Incidence of
basal cell carcinoma
Nurses Health Study, USA
Women aged 30–55
3060
Z 15 g/day
Health Professionals
Follow-up Study, USA
Men aged 40–75
3028
0.56 (0.29–1.08) red wine Fung et al., 2002
1.05 (0.54–2.04) beer
1.31 (0.95–1.80) spirits
Age, sex, smoking, education, BMI, physical activity, other alcoholic
beverages
Age, residence, BMI,
smoking, sun exposure,
sunscreen use, total calories, other alcoholic
beverages
1.00 (0.67–1.49) red wine
1.00 (0.72–1.38) beer
1.11 (0.94–1.31) spirits
a
Abstainers represent the reference category; the RR reported here corresponds to the higher degree of adjustments for confounding. Abbreviations: BMI, body mass index; HRT, hormone replacement therapy.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Wine and cancer Bianchini and Vainio 419
Death for cancer
Cancer incidence and low alcohol consumption. Case-control studiesa
Endpoint
Study, country
Population
No of
cases
Alcohol intake
Relative riskb
( ± 95% confidence interval)
Reference
Adjustment
Incidence of non-Hodgkin
lymphoma
Population-based,
USA
Men from 8 cancer
registries, aged 32–60
960
Z 1 drink/day
1–2 drinks/day
1–2 drinks/day
0.4 (0.2–0.9) wine
1.2 (0.8–1.7) beer
1.1 (0.7–1.8) spirits
Briggs et al., 2002
Age, ethnicity, cancer registry, smoking, education,
other alcoholic beverages
Incidence of adenocarcinoma of the
esophagus
Population-based,
USA
Men and women from
3 geographical areas,
aged 30–79
554
4–7 drinks/week
5–12 drinks/week
5–14 drinks/week
0.6 (0.4–0.9) wine
0.6 (0.3–0.9) beer
1.2 (0.8–1.9) spirits
Gammon et al., 1997
Age, sex, centre, race, BMI,
income, smoking, other
alcoholic beverages
Incidence of adenocarcinoma of the
esophagus
Population-based,
USA
Men from 3 centers
174
3–13 drinks/week
8–14 drinks/week
8–14 drinks/week
0.8 (0.4–1.5) wine
0.7 (0.4–1.2) beer
1.8 (1.0–3.2) spirits
Brown et al., 1994
Age, area, income, smoking,
other alcoholic beverages
Incidence of breast
cancer
Selected controls,
France
Population-based,
USA
Premenopausal women
aged 30–50
Women (pre- and
post-menopausal)
154
4 l/month
1 l/month
Z 28 drinks/month
1.52 (0.88–2.63) red wine Viel et al., 1997
1.43 (0.62–3.33) beer
0.8 (0.51–1.25) wine
Freudenheim et al., 1995
1.37 (0.83–2.25) beer
0.84 (0.52–1.38) spirits
Population-based,
Spain
Women aged 18–75
762
Hospital-based,
Italy
Women aged 26–74
437
0.7–5.12 g/day
0.8–3.3 g/day
0.5–1.4 g/day
r 3 drinks/day
yes vs. no
yes vs. no
1.0 (0.8–1.4) wine
1.2 (0.9–1.7) beer
1.0 (0.6–1.7) spirits
1.16 (0.85–1.59) wine
1.32 (0.82–2.13) beer
1.44 (0.92–2.23) spirits
Hospital-based,
France
Women (mean age 58)
500
< 80 g/week
< 80 g/week
< 10 g/week
1.19 (P for trend = 0.02)
wine
1.29 (P for trend = 0.02)
beer
0.86 (N.S.) spirits
Incidence of
endometrial cancer
Hospital-based,
Italy
Women aged 28–74
726
> 0– r 1 drinks/day
yes vs. no
yes vs. no
1.1 (0.9–1.4) wine
0.7 (0.5–1.1) beer
1.6 (1.1–2.2) spirits
Parazzini et al., 1995
Age, education, BMI, smoking, reproductive factors,
HRT, diabetes, hypertension, other alcoholic beverages
Incidence of
colorectal cancer
Population-based,
Sweden
Men and women > 40
569
1.0–9.9 g/day
0.9 (0.6–1.1) wine
0.9 (0.7–1.2) beer
1.0 (0.6–1.7) spirits
Gerhardsson de Verdier
et al., 1993
Age, sex, BMI, energy intake, smoking, physical
activity
740
Caloric intake, parity
Age, education, reproductive factors, family history,
BMI, caloric intake, other
alcoholic beverages.
Martin-Moreno et al., 1993 Age, region, SES, BMI,
family history, reproductive factors, energy intake
La Vecchia et al., 1985
Age, education, smoking,
reproductive
factors,
BMI, smoking, HRT, other
alcoholic beverages
Lê et al., 1984
Reproductive factors, history, SES, other alcoholic
beverages
a
Only studies considering at least three categories of wine consumption are reported.
Abstainers represent the reference category; the RR reported here corresponds to the higher degree of adjustments for confounding. Abbreviations: BMI, body mass index; HRT, hormone replacement therapy; SES,
socioeconomic status.
b
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420 European Journal of Cancer Prevention 2003, Vol 12 No 5
Table 2
Wine and cancer Bianchini and Vainio 421
4 litres of red wine per month, corresponding to
approximately one drink per day (RR = 1.52; CI, 0.88–
2.63) (Viel et al., 1997) and in women consuming less than
80 g wine per week (P for trend, 0.02) (Lê et al., 1984).
Other studies showed that wine did not increase the risk
of breast cancer (Freudenheim et al., 1995; MartinMoreno et al., 1993).
Altogether, these studies lack consistencies in identifying
a specific beverage as more beneficial in cancer prevention. It is possible that the beverage more widely
consumed in a country would result in a stronger
beneficial effect in such population, also because this is
related to other lifestyle factors (Rimm, 1996). Nevertheless, there is suggestion of a J-shaped association
between low consumption of wine with cancer, although
it does not provide any proof of causality. These
epidemiological studies may suffer from selection bias,
including the presence of former drinkers in the group of
abstainers, or the prevalence of higher morbidity among
abstainers at baseline. Current instead of past consumption of alcohol has sometimes been recorded and residual
confounding could also explain the effect. For example, it
is possible that a preferential consumption of wine,
compared with other beverages, might be confounded by
lifestyle factors, including diet and smoking, by social
class, or by a different drinking pattern. Wine is
consumed particularly in combination with a Mediterranean diet, where fruits and vegetables (putative protective factors against cancer and cardiovascular disease) are
generally present in large amounts. Thus moderate
drinking may be an indicator of healthy lifestyle. On
the other hand, most studies have controlled for smoking
and education, factors associated with alcohol drinking.
Risk differences between various alcoholic beverages
could also be ascribed to a corresponding different
pattern of drinking. It has been suggested that not only
the amount but also the frequency of drinking may be
relevant. For example, the risk of a major coronary event
was lower in subjects consuming alcohol on five or six
days per week than in subjects consuming the same
amount of alcohol one or two days a week (McElduff and
Dobson, 1997). A regular intake of small amount of
alcohol seems to be more associated with wine drinking,
which is generally consumed with meals, than other
alcoholic beverages. A large cohort study conducted in
Italy has shown that drinking wine outside meals is
associated with higher mortality compared with drinking
wine during meals (Trevisan et al., 2001). In addition, a
lower mortality from all causes, cardiovascular disease and
coronary heart disease was observed in men drinking wine
with meals compared to non-drinkers.
Polyphenols and resveratrol
What could be responsible for the particular protective
effect, if it exists, of wine against cancer development?
The protective effect of moderate alcohol consumption
on cardiovascular disease has been mainly attributed to
the ability of ethanol to increase high-density lipoprotein
(HDL) cholesterol and to decrease platelet aggregation
(Criqui et al., 1987; Renaud and de Lorgeril, 1992). As
ethanol has been shown to act as a co-carcinogen,
increasing the activation of carcinogens, oxidative stress
and cell proliferation (Simanowski et al., 1986; Garro and
Lieber, 1990; Cahill et al., 1997) it is likely that the
beneficial effects of alcohol, particularly red wine, on
cancer are mainly due to the presence of substances other
than ethanol. Polyphenolic compounds which are present
10–20 times higher in red wine than in white wine
(Soleas et al., 1997) have been suggested as protective
factors. This category includes flavonoids (flavones,
flavanones, anthocyanins, catechins) and non-flavonoid
phenols. These compounds are widely present in fruits,
vegetables, grains, tea and wine; however, their availability seems much higher in wine, where polyphenols are
present in monomeric form, in contrast to polymeric form
in solid foodstuff (Goldberg, 1995). Several therapeutic
properties of polyphenols have been described, including
increased levels of HDL cholesterol, decreased platelet
aggregation and endothelial adhesion, antioxidant activity,
free radical scavenging, inhibition of cell proliferation and
angiogenesis (Soleas et al., 1997; Nijveldt et al., 2001).
A specific non-flavonoid polyphenolic compound, resveratrol (3,5,40 -trihydroxystilbene), mainly in its trans-isoform, has attracted the attention of recent research as an
agent responsible for beneficial effects of wine. Apart
from its occurrence in peanuts, this compound is present
at significant levels only in red wine. Resveratrol is
synthesized in the skin of grapes in response to external
injuries, reaching concentrations of 50–100 mg/g (Jang
et al., 1997). Its concentration in wine depends on
fermentation time of the grapes, and therefore, as skins
are removed much earlier for the preparation of white
wine, red wine contains much higher amounts of
resveratrol. The concentration of resveratrol is highly
variable depending on the type of wine; values up to
0.1 mg/mL in white wines and 0.65 mg/mL in red wines
have been reported (Siemann and Creasy, 1992; Goldberg
et al., 1995). Higher values for red wines, up to 5 mg/mL,
have also been reported (McMurtrey et al., 1994; Pezet
et al., 1994; Goldberg et al., 1995; Ector et al., 1996).
Mechanistic pathways
Several mechanistic pathways that could account for the
cancer-preventive activity of resveratrol have been
explored, suggesting that resveratrol may affect either
initiation or promotion and progression of the cancer
process (Jang et al., 1997). Relevant hypotheses include
inhibition of cytochrome P450 enzymes, antioxidant and
anti-inflammatory activities, and effects on cell cycle, cell
proliferation and apoptosis (Gusman et al., 2001).
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
422 European Journal of Cancer Prevention 2003, Vol 12 No 5
Resveratrol inhibits CYP1A1, thus inhibiting the metabolic activation of pro-carcinogens, such as the polycyclic
aromatic hydrocarbons, benzo[a]pyrene and dimethylbenz[a]anthracene (Chun et al., 1999; Ciolino and Yeh,
1999; Mollerup et al., 2001). The effect seems to be due
either to direct inhibition of the enzymatic activity or to
the inhibition of signal transduction mediated by the aryl
hydrocarbon receptor (Ciolino and Yeh, 1999).
The cancer preventive activity of resveratrol could also be
attributed to its antioxidant properties. Resveratrol
reduces oxidative damage induced by H2O2 in calf
thymus DNA (Burkhardt et al., 2001) and in several
cancer cell lines (Damianaki et al., 2000; Sgambato et al.,
2001). Levels of 8-hydroxy-20 -deoxyguanosine, a known
marker of oxidative DNA damage, are also reduced in vivo
by administration of resveratrol (Cadenas and Barja, 1999;
Mizutani et al., 2001).
The anti-inflammatory activity of resveratrol seems
mainly related to the inhibition of cyclooxygenases,
although results have been inconsistent. Jang et al.
(1997) reported that resveratrol selectively inhibited
the expression of COX-1, but not the inducible form of
the enzyme COX-2 that is more related to tumorigenesis.
On the contrary, inhibition of the transcription and the
expression of COX-2 have been reported (Subbaramaiah
et al., 1998). The inhibition of COX-2 seems responsible
for the protection against experimental carcinogenesis.
For example, the reduced number or decreased size of
oesophageal tumours induced by N-nitrosomethylbenzylamine in rats treated with resveratrol could be explained
by the inhibition of the expression of COX-1 and COX-2
and the decrease in prostaglandin E2 levels (Li et al.,
2002). Resveratrol also suppresses DMBA-induced mammary carcinogenesis, and this effect correlated with
down-regulation of COX-2; the down-regulation of
COX-2 seems also to be linked to suppression of the
activation of the transcriptor factor NF-kB (Banerjee et al.,
2002). This factor is inactive in the cytoplasm of normal
cells due to binding with the inhibitor protein IkB; when
activated, it can translocate to the nucleus and induce the
expression of genes associated with the inflammatory
processes and the development of cancer, such as altered
cell growth, immune or inflammatory responses (Baldwin,
1996). The inhibitory activity of resveratrol on NF-kB
seems to be due to the inhibition of the IkB kinase
activity (Holmes-McNary and Baldwin, 2000).
Several studies have attributed the anti-tumour activity
of resveratrol to its effect on the cell cycle, cell
proliferation and apoptosis; these effects have been
recently reviewed (Gusman et al., 2001). The effect on
cell cycle progression is highly variable, depending on the
experimental system (Della Ragione et al., 1998; Schneider et al., 2000; Park et al., 2001; Joe et al., 2002). Cell
proliferation is inhibited in a dose-dependent manner in
different human cancer cell lines, and the effect seems
rather specific for malignant cells (Clement et al., 1998).
The anti-proliferative effect of resveratrol may be due to
inhibition of polyamine biosynthesis through inhibition of
ornithine decarboxylase activity (Schneider et al., 2000) or
through inhibition of ribonucleotide reductase (Fontecave et al., 1998). Resveratrol has also been shown to
decrease the proliferation of breast cancer cell lines
(Mgbonyebi et al., 1998; Lu and Serrero, 1999; Damianaki
et al., 2000; Levenson et al., 2003), although increased
proliferation was also reported (Gehm et al., 1997;
Schmitt et al., 2002). The effects on cell growth are
possibly mediated by an interaction with the oestrogen
receptor (ER); however this seems not to be the only
mechanism, as inhibition of proliferation has been
observed in both ER + and ER-cells (Mgbonyebi et al.,
1998; Damianaki et al., 2000, Levenson et al., 2003).
Several studies have reported an induction of apoptosis
by resveratrol (Clement et al., 1998; Huang et al., 1999;
Surh et al., 1999; Tessitore et al., 2000; Lu et al., 2001;
Mahyar-Roemer et al., 2001; Joe et al., 2002), although
conflicting results have been obtained regarding the
mechanism associated with such induction. Cell death
seems to occur only in tumour cells and has been shown
to involve the CD95-CD95L system (Clement et al.,
1998). Resveratrol could inhibit apoptosis through
induction of P53 activity (Huang et al., 1999; Lu et al.,
2001; She et al., 2001; Narayanan et al., 2003) but a p-53
independent pathway has also been proposed (MahyarRoemer et al., 2001). Cyclins (D1, A, B1), p21 expression,
the apoptosis agonist bax and the anti-apoptotic bcl-2
have also been reported to be involved (Surh et al.,
1999; Tessitore et al., 2000; Mahyar-Roemer et al., 2001;
Joe et al., 2002).
The similarity between resveratrol and the synthetic
oestrogen diethylstilboestrol has raised questions regarding its oestrogenic activity. The oestrogenic properties of
resveratrol have been studied quite extensively, although
results are still contradictory. Resveratrol is able to bind to
the ER, although with lower affinity than oestradiol; the
affinity to ERa and ERb seems comparable (Bowers et al.,
2000). This interaction can result in an agonistic,
antagonistic or a mixed effect. In ER + MCF-7 cells,
resveratrol alone acts as an agonist of the receptor (Gehm
et al., 1997; Basly et al., 2000; Bhat et al., 2001; Schmitt
et al., 2002) and acts as an antagonist when it is
administered in combination with oestradiol (Lu and
Serrero, 1999; Bhat et al., 2001). This antagonistic effect
has been reported with other, but not all, mammary cell
lines (Bhat et al., 2001), but it has also been questioned
(Levenson et al., 2003). A super-agonist effect has been
observed when resveratrol was co-administered with
oestradiol (Gehm et al., 1997), although this has not
been confirmed by others (Klinge et al., 2003). The
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Wine and cancer Bianchini and Vainio 423
antagonist effect seems specific for the oestrogen
receptor a, but not the oestrogen receptor b (Bowers et
al., 2000). This may have relevant implications, as the
presence of a or b receptors differs between normal, premalignant and malignant breast tissues (Roger et al.,
2001). It is noteworthy that resveratrol decreases the
multiplicity and delays the occurrence of N-methyl-Nnitrosourea-induced mammary tumours in the rat (Bhat et
al., 2001). The observation that resveratrol suppresses the
incidence of tumours during early stages (up to 40 days),
and that pre-malignant lesions are mainly composed of
ER + cells, suggest that preventive effects of resveratrol
could be mediated by its anti-oestrogenic properties. As
resveratrol seems to have anti-proliferative and antioestrogenic effect on endometrial adenocarcinoma cells
(Bhat and Pezzuto, 2001), it has been proposed as a new
phytoestrogen, showing a tissue-specific profile in modulating the oestrogen receptor. It has recently been
suggested that substances present in red wine, other than
resveratrol, might have oestrogenic effects (Klinge et al.,
2003).
accumulating for a beneficial effect, or at least for lack of
a harmful effect on the development of certain cancers.
The protection appears more pronounced with wine, and
it is speculated that resveratrol, a natural component
specifically present in red wine may be the main
component responsible for this effect. Although these
findings might be significant for light drinkers from an
individual point of view, recommending regular consumption of small doses of wine for the general public is
inappropriate for many reasons.
In order to establish a causal relationship between
consumption of wine or resveratrol and prevention of
disease, a beneficial effect should be demonstrated in
intervention studies, in which known doses of wine and/
or resveratrol are given for a precise duration. Relevant
surrogate biomarkers of effect, instead of final disease
endpoints, could be used. Further investigation in the
mechanisms of action of putative protective agents and
the causal association with cancer, as well as studies on
the absorption, metabolism and toxicity are also needed
before any wider use in humans can be considered.
Availability in vivo
Resveratrol might represent a promising agent to be
tested for cancer chemo-preventive activity in clinical
trials. The concentrations of resveratrol shown to have
biological activity in vitro range, approximately, from 5–
50 mM, although higher levels seem to be needed for
some effects. The concentration of resveratrol in wine is
3–20 mM (0.65 mg/L to 5 mg/L); the percentage available
for an effect in vivo is still not clear, as only limited data
on the kinetics of resveratrol have been published.
Studies in isolated rat small intestine have shown that
resveratrol is mainly conjugated with glucuronic acid
during its absorption through the intestinal wall (Andlauer et al., 2000; Kuhnle et al., 2000). A recent study in
rats has shown that resveratrol is available at 38% after
oral administration and confirmed that resveratrol undergoes in vivo extensive glucuronidation (Marier et al.,
2002); it was also shown that important enterohepatic recirculation occurs, although its contribution to the
pharmacological effect remains unclear. Another study
showed that resveratrol, following administration to rats,
rapidly reached a peak concentration in blood and at least
50% of the compound was absorbed (Soleas et al., 2001a).
Following oral administration to mice, resveratrol remained mostly in the intact form and penetrated tissues,
mainly liver and kidney (Vitrac et al., 2003). However only
10–15% of resveratrol administered in white wine to
humans is absorbed and may undergo metabolism before
excretion in the urine (Soleas et al., 2001b).
Conclusions
Regular intake of low doses of alcohol seems to be
associated with reduced total mortality and reduced risk
and mortality from cardiovascular disease. Evidence is
In addition, recommending a change in alcohol drinking
habits, especially among non-drinkers, could have deleterious effect on those prone to addiction, leading to
excessive drinking and to all the negative social and
cultural consequences of such behaviour. An alternative
approach could be to adopt an upper ‘safe’ limit of alcohol
consumption. For example, the National Health and
Medical Research Council in Australia advises women and
men not to consume more than two or four drinks per day,
respectively (National Health and Medical Research
Council, 1992).
In conclusion, drinking one or two glasses of wine per day
seems reasonably safe, and there are suggestions of
beneficial effects on total mortality and on mortality from
cardiovascular disease, and possibly some cancers. These
effects, however, cannot be generalized to population
recommendations. The beneficial and deleterious effects
should be weighted up on an individual basis, taking into
account individual characteristics, including lifestyle and
risk factors, and recommendation for general public
should still be to refrain from drinking.
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