Current epidemiological knowledge about the role of flavonoids in prostate carcinogenesis
Numerous experimental studies have demonstrated anticancer action of polyphenolic plant metabolites. However, data about associations between dietary intake of plant-derived flavonoids and prostate cancer risk are still sparse and inconsistent. This minireview compiles the epidemiological findings p...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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| Cite this: | Current epidemiological knowledge about the role of flavonoids in prostate carcinogenesis / K. Sak // Experimental Oncology. — 2017 — Т. 39, № 2. — С. 98–105. — Бібліогр.: 38 назв. — англ. |
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| citation_txt | Current epidemiological knowledge about the role of flavonoids in prostate carcinogenesis / K. Sak // Experimental Oncology. — 2017 — Т. 39, № 2. — С. 98–105. — Бібліогр.: 38 назв. — англ. |
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| description | Numerous experimental studies have demonstrated anticancer action of polyphenolic plant metabolites. However, data about associations between dietary intake of plant-derived flavonoids and prostate cancer risk are still sparse and inconsistent. This minireview compiles the epidemiological findings published to date on the role of flavonoids in prostate tumorigenesis, discusses the reasons of inconsistencies and elicits the promising results for chemoprevention of this malignancy. Long-term consumption of high doses of soy isoflavones can be the reason of markedly lower clinically detectable prostate cancer incidence among Asian men compared to their counterparts in the Western world. The ability to metabolize daidzein to equol, the most biologically active isoflavone, by the certain intestinal bacteria also seems to contribute to this important health benefit. The increasing incidence rate of prostate cancer related to adoption of westernized lifestyle and dietary habits makes the issue of chemoprevention ever more important and directs the eyes to specific food components in the Eastern diet. If further large-scale epidemiological studies will confirm the protective effects of isoflavones against prostate cancer, this could provide an important way for prostate cancer prevention, as diet is a potentially modifiable factor in our behavioral pattern.
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98 Experimental Oncology 39, 98–105, 2017 (June)
CURRENT EPIDEMIOLOGICAL KNOWLEDGE ABOUT THE ROLE
OF FLAVONOIDS IN PROSTATE CARCINOGENESIS
K. Sak*
NGO Praeventio, Näituse 22–3, Tartu 50407, Estonia
Numerous experimental studies have demonstrated anticancer action of polyphenolic plant metabolites. However, data about as-
sociations between dietary intake of plant-derived flavonoids and prostate cancer risk are still sparse and inconsistent. This mini-
review compiles the epidemiological findings published to date on the role of flavonoids in prostate tumorigenesis, discusses the
reasons of inconsistencies and elicits the promising results for chemoprevention of this malignancy. Long-term consumption of high
doses of soy isoflavones can be the reason of markedly lower clinically detectable prostate cancer incidence among Asian men
compared to their counterparts in the Western world. The ability to metabolize daidzein to equol, the most biologically active iso-
flavone, by the certain intestinal bacteria also seems to contribute to this important health benefit. The increasing incidence rate
of prostate cancer related to adoption of westernized lifestyle and dietary habits makes the issue of chemoprevention ever more
important and directs the eyes to specific food components in the Eastern diet. If further large-scale epidemiological studies will
confirm the protective effects of isoflavones against prostate cancer, this could provide an important way for prostate cancer pre-
vention, as diet is a potentially modifiable factor in our behavioral pattern.
Key Words: chemoprevention, epidemiological findings, flavonoids, plant metabolites, prostate cancer.
The incidence rate of clinically detectable prostate
cancer is historically markedly lower in Asian coun-
tries, such as Japan, China, India, Singapore or Korea,
compared to the Western world, including men living
in American, European countries or Canada [1–9]. This
age-adjusted difference between Asian and Western
populations can reach even 10- to 90-fold [10–12].
However, in parallel to adoption of westernized habits
among Japanese men, the incidence rate of prostate
tumors is gradually rising [1, 6, 7, 9]. Also, Japanese mi-
grants to the United States as well as foreign-born Asian
Americans reveal an increased incidence of prostate
neoplasms [3, 6, 10, 11, 13–16]. On the contrary, the in-
cidence of clinically undetectable or latent prostate can-
cers in autopsy studies is rather similar between men
from Asian and American countries, suggesting that
some components in the Asian diet can block progres-
sion of latent cancers to the more advanced form [3, 6,
8, 14]. Therefore, the etiology of prostate tumor might
involve environmental factors, such as dietary habits,
which can play a major role in the pathogenesis of this
malignancy [1, 3–6, 11–20]. A traditional Asian diet
is rich in soy-derived phytoestrogens or isoflavones that
have been related to the lower incidence of prostate
cancer in this region [3, 7–9, 14, 21].
Plant-based food items contain various phyto-
chemicals, including flavonoids, with anticarcinogenic
properties [18]. These polyphenolic compounds may
influence prostate tumorigenesis through multiple
different mechanisms; flavonoids have been shown
to exhibit antioxidant, antiinflammatory, antiprolifera-
tive, proapoptotic, antiangiogenic and antimetastatic
activities [13, 18, 22]. Although numerous experimen-
tal cell culture and animal studies have demonstrated
different effects of these plant metabolites against
prostate cancer, findings from epidemiological studies
are still limited and far from definite [6, 12, 16, 19, 21,
23–26]. To comprehend the current state of epide-
miological evidence on the role of various flavonoids
on prostate tumorigenesis, the findings published
to date about associations between dietary intake
of flavonoids and the risk of prostate cancer were
compiled and are analyzed in this minireview. In addi-
tion, the blood and urinary biomarker data are included
in the survey. These data are presented in Tables 1–3.
Also, the potential factors for inconsistencies are put
forward and discussed.
EPIDEMIOLOGICAL DATA ABOUT
THE ROLE OF FLAVONOIDS ON PROSTATE
CANCER RISK
Case-control studies
No statistically significant associations with the
risk of prostate cancer were found for total flavonoids
or flavonoid subclasses, including flavones, flavonols,
flavanones, flavanols, isoflavones and anthocyanidins
in Italian population, showing no protective effects
of flavonoids against prostate tumorigenesis [21]. These
results were in general agreement with two other case-
control studies, revealing no significant relationships be-
tween intake of flavones (apigenin, luteolin) and flavonols
(kaempferol, myricetin) and prostate cancer incidence
among American men [18, 27]. However, a suggestive
inverse association was still reported for flavonol quer-
cetin with a 36% decrease in prostate cancer risk for
men in the highest quartile of quercetin consumption
compared to those in the lowest quartile of intake [18].
Similarly to the work with Italian men, no overall re-
lationships between consumption of total or individual
isoflavones (genistein, daidzein) and prostate cancer
risk were observed also in Swedish [17, 28], Scot-
tish [5], or English population [12, 29]. However, these
results are different from the findings of case-control
studies conducted with Japanese [1] and Chinese
men [15], which observed a protective effect of intake
Submitted: March 13, 2017.
*Correspondence: E-mail: katrin.sak.001@mail.ee
Exp Oncol 2017
39, 2, 98–105
REVIEW
Experimental Oncology 39, 98–105, 2017 (June)39, 98–105, 2017 (June) (June) 99
of both genistein and daidzein against prostate cancer.
At that, Nagata et al. described a significant 42% and
45% reduction of prostate cancer risk with high dietary
consumption of genistein and daidzein, respectively [1],
and Lee et al. reported a 47% and 44% decrease in the
tumor risk with high consumption of these isoflavones,
respectively [15]. These results demonstrate that iso-
flavones can indeed contribute to a protective effect
against prostate neoplasms. Also, Strom et al. observed
some suggestive, still non-significant, lowering in pros-
tate cancer incidence with high dietary consumption
of daidzein and genistein among American men [27].
As the daily intake of soy foods in European countries
is very low compared to Asian men (this difference can
be even about hundredfold), it is possible that these lev-
els were too low for a preventive effect against prostate
cancer to be become obvious [12, 21] (see Table 1).
Prospective cohort studies
Using the prospective cohort study design, no signif-
icant inverse associations with prostate cancer risk were
found for intake of total flavonoids as well as flavonoid
subclasses flavones, flavanones and anthocyanidins
in different populations, including American, Hawaiian,
Dutch, and Finnish men [23, 30–33]. Although Wang
et al. observed a weak positive relationship with intake
of total flavonoids, flavanols or isoflavones, but also
flavonols or flavanones with overall prostate cancer
incidence, the relative risk varied over follow-up time
and the positive association disappeared when the
cases diagnosed during the first two follow-up years
were excluded from the analysis [16]. The authors pro-
posed that such pattern could be affected by behaviors
associated with prostate cancer screening [16]. For
flavonols, Knekt et al. found a statistically significant
57% decrease in prostate cancer risk with high dietary
intake of myricetin among Finnish men; but no risk
modification by other common flavonols like kaempferol
or quercetin [31]. Geybels et al. conducted a prospec-
tive cohort study with Dutch men and stratification of the
analysis by cancer stage revealed a significant inverse
association between intake of both kaempferol and
myricetin (not quercetin) with stage IV prostate can-
cer and not with overall or non-advanced neoplasms
(stage I/II tumors) [33]. Similar trend became evident
also for total flavanols and epicatechin (not catechin),
as the significant inverse association was found for
advanced stage prostate tumor and not non-advanced
cancer [33].
Although both Park et al. and Kurahashi et al.
reported no significant relationships between intake
of individual isoflavones (genistein, daidzein) and total
prostate cancer risk [3, 23], Kurahashi et al. still found
Table 1. Epidemiological case-control studies on dietary intake of flavonoids and prostate cancer risk
Flavonoid
subclass
Certain
compound Studya Popula-
tion
Con-
trolsb Cases/controls Intake comparison
(low vs high, mg/day)c
Multivariate-
adjusted OR/RRd
p for
trende
Age,
years
Refe-
rence
Flavonoids Italian HB 1294/1451 (Q5) 1.20 (0.92–1.58) 0.44 46–74 [21]
Flavones Italian HB 1294/1451 (Q5) 1.09 (0.85–1.40) 0.88 46–74 [21]
Flavones Apigenin American HB 83/107 0.83 (0.45–1.51) 0.54 [27]
Flavones Luteolin American HB 83/107 0.83 (0.45–1.51) 0.54 [27]
Flavonols Italian HB 1294/1451 (Q5) 1.23 (0.95–1.61) 0.26 46–74 [21]
Flavonols Kaempferol WNYDS American PB 433/538 < 1.4475 vs > 6.0568 (Q4) 0.83 (0.58–1.18) 0.80 [18]
Flavonols Kaempferol American HB 83/107 0.77 (0.42–1.43) 0.41 [27]
Flavonols Myricetin American HB 83/107 1.12 (0.61–2.06) 0.70 [27]
Flavonols Quercetin WNYDS American PB 433/538 < 10.5663 vs >25.5626 (Q4) 0.64 (0.44–0.92) 0.15 [18]
Flavonols Quercetin American HB 83/107 0.96 (0.53–1.76) 0.90 [27]
Flavanones Italian HB 1294/1451 (Q5) 0.96 (0.75–1.23) 0.56 46–74 [21]
Flavanols Italian HB 1294/1451 (Q5) 1.30 (1.01–1.69) 0.48 46–74 [21]
Isoflavones EPIC-Norfolk English PB 203/800 0.89 (0.72–1.11) 0.29 40–79 [29]
Isoflavones Italian HB 1294/1451 (Q5) 0.98 (0.76–1.26) 0.34 46–74 [21]
Isoflavones PCANDIET Scottish PB 433/483 < 0.5811 vs > 1.9828 (Q4) 1.18 (0.79–1.75) 0.87 50–74 [5]
Isoflavones CAPS Swedish PB 1499/1130 0.0008 vs 0.113 (Q4) 0.99 (0.77–1.28) 0.68 36–79 [17]
Isoflavones CAPS Swedish PB 1431/1081 0.0008 vs 0.113 (Q4) 0.99 (0.77–1.28) 0.95 35–79 [28]
Isoflavones Japanese HB 200/200 < 30.5 vs ≥ 89.9 (Q4) 0.42 (0.24–0.72) <0.01* 59–73 [1]
Isoflavones Genistein American HB 83/107 0.71 (0.39–1.30) 0.26 [27]
Isoflavones Genistein EPIC-Norfolk English PB 203/800 0.90 (0.74–1.10) 0.31 40–79 [29]
Isoflavones Genistein EPIC-Norfolk English PB 89/178 1.07 (0.84–1.37) 0.575 45–75 [12]
Isoflavones Genistein CAPS Swedish PB 1499/1130 0.00019 vs 0.0694 (Q4) 0.97 (0.75–1.26) 0.09 36–79 [17]
Isoflavones Genistein Chinese PB 133/265 < 17.9 vs > 62.0 (Q4) 0.53 (0.29–0.97) 0.058 50–89 [15]
Isoflavones Genistein Japanese HB 200/200 < 1.1 vs ≥ 2.5 (Q4) 0.58 (0.34–0.97) 0.04* 59–73 [1]
Isoflavones Daidzein American HB 83/107 0.57 (0.31–1.05) 0.07 [27]
Isoflavones Daidzein EPIC-Norfolk English PB 203/800 0.92 (0.69–1.22) 0.56 40–79 [29]
Isoflavones Daidzein EPIC-Norfolk English PB 89/178 1.06 (0.84–1.64) 0.630 45–75 [12]
Isoflavones Daidzein CAPS Swedish PB 1499/1130 0.00037 vs 0.0431 (Q4) 1.22 (0.92–1.62) 0.70 36–79 [17]
Isoflavones Daidzein Chinese PB 133/265 < 10.0 vs > 36.3 (Q4) 0.56 (0.31–1.04) 0.116 50–89 [15]
Isoflavones Daidzein Japanese HB 200/200 < 0.8 vs ≥ 1.9 (Q4) 0.55 (0.32–0.93) 0.02* 59–73 [1]
Isoflavones Biochanin A American HB 83/107 0.92 (0.50–1.70) 0.79 [27]
Isoflavones Biochanin A EPIC-Norfolk English PB 203/800 0.89 (0.69–1.14) 0.34 40–79 [29]
Isoflavones Formononetin American HB 83/107 0.99 (0.54–1.81) 0.98 [27]
Isoflavones Formononetin EPIC-Norfolk English PB 203/800 0.97 (0.83–1.13) 0.70 40–79 [29]
Isoflavones Glycitein EPIC-Norfolk English PB 203/800 0.88 (0.67–1.15) 0.34 40–79 [29]
Isoflavones Equol EPIC-Norfolk English PB 203/800 1.31 (1.00–1.71) 0.050* 40–79 [29]
Anthocyanidins Italian HB 1294/1451 1.18 (0.91–1.53) 0.22 46–74 [21]
Note: aCAPS — The Cancer Prostate Sweden Study; EPIC — The European Prospective Investigation into Cancer and Nutrition; PCANDIET — The Prostate
Cancer and Diet Study; WNYDS — The Western New York Diet Study.
bHB — hospital-based; PB — population-based.
cQ4 — quartiles; Q5 — quintiles.
dOR — odds ratio; RR — relative risk.
eStatistically significant effects (p for trend < 0.05) are marked by asterisk.
100 Experimental Oncology 39, 98–105, 2017 (June)
Table 2. Epidemiological prospective cohort studies on dietary intake of flavonoids and prostate cancer risk
Flavonoid
subclass
Certain
compound Stu dya Popula-
tion
Medi-
an fol-
low-up
(years)
Cases/
cohort
Intake comparison
(low vs high,
mg/day)b
Multivariate-
adjusted RR/HRc
p for
trendd Commentse Refe-
rence
Flavonoids CPS-II American 7.8 3974/
43,268
< 126.6 vs
≥ 359.5 (Q5)
1.11 (1.01–1.23) 0.02* 50–74 y; positive associ-
ation for high grade can-
cer within the first 2 y of fol-
low-up, suggestive inverse
association after excluding
these first 2 y; no associa-
tions with advanced cancer
[16]
Flavonoids MEC American,
Hawaiian
8.0 4404/
82,483
< 1.6 vs ≥ 7.2/
1000 kcal (Q5)
0.93 (0.83–1.04) 0.17 45–75 y; multiethnic; no in-
verse association regard-
less of stage
[23]
Flavonoids NLCS Dutch 17.3 3362/
58,279
13.1 vs 40.6 (Q4) 1.00 (0.84–1.18) 0.74 55–69 y; no significant ef-
fect modification by can-
cer stage
[33]
Flavonoids FMC Finnish 24.0 62/9959 < 2.1 vs > 4.8 (Q4) 1.39 (0.56–3.46) 15–99 y [30]
Flavonoids FMC Finnish 30.0 95/5218 4.3 vs 26.9 (Q4) 1.11 (0.61–2.01) 0.57 [31]
Flavonoids KIHD Finnish 16.2 138/2590 9.1 vs 416.3 (Q4) 1.16 (0.58–2.34) 0.831 42–60 y [32]
Flavones CPS-II American 7.8 3974/
43,268
< 0.5 vs
≥ 2.2 (Q5)
1.05 (0.95–1.16) 0.19 50–74 y; no associations for
high grade or advanced can-
cers within or without the first
2 y of follow-up
[16]
Flavones KIHD Finnish 16.2 138/2590 (Q4) 0.71 (0.30–1.65) 0.561 42–60 y [32]
Flavonols CPS-II American 7.8 3974/
43,268
< 8.9 vs
≥ 20.5 (Q5)
1.10 (0.99–1.21) 0.05* 50–74 y; suggestive pos-
itive association for high
grade cancer within the first
2 y of follow-up, not after
excluding these first 2 y;
no associations with ad-
vanced cancer
[16]
Flavonols KIHD Finnish 16.2 138/2590 (Q4) 1.53 (0.72–3.23) 0.585 42–60 y [32]
Flavonols Kaempferol NLCS Dutch 17.3 3362/
58,279
2.5 vs 11.2 (Q4) 0.98 (0.83–1.16) 0.73 55–69 y; significant inverse
association for stage IV can-
cer [0.78 (0.61–1.00),
p = 0.03*], not for non-ad-
vanced cancer
[33]
Flavonols Kaempferol FMC Finnish 30.0 95/5218 0.1 vs 0.8 (Q4) 1.03 (0.53–2.02) 0.54 [31]
Flavonols Myricetin NLCS Dutch 17.3 3362/
58,279
0.4 vs 2.6 (Q4) 0.89 (0.75–1.05) 0.41 55–69 y; signifi-
cant inverse associa-
tion for stage IV can-
cer [0.71 (0.55–0.91),
p = 0.03*], not for non-ad-
vanced cancer
[33]
Flavonols Myricetin FMC Finnish 30.0 95/5218 0 vs 0.11 (Q4) 0.43 (0.22–0.86) 0.002* [31]
Flavonols Quercetin NLCS Dutch 17.3 3362/
58,279
8.8 vs 28.5 (Q4) 1.01 (0.85–1.19) 0.98 55–69 y; no significant ef-
fect modification by can-
cer stage
[33]
Flavonols Quercetin FMC Finnish 30.0 95/5218 1.5 vs 3.9 (Q4) 0.76 (0.40–1.42) 0.35 [31]
Flavanones CPS-II American 7.8 3974/
43,268
< 7.5 vs
≥ 38.2 (Q5)
1.08 (0.98–1.20) 0.31 50–74 y; positive associ-
ation for high grade can-
cer within the first 2 y of fol-
low-up, not after excluding
these first 2 y; no associa-
tions with advanced cancer
[16]
Flavanones KIHD Finnish 16.2 138/2590 (Q4) 0.90 (0.37–2.20) 0.518 42–60 y [32]
Flavanones Hesperetin FMC Finnish 30.0 95/5218 0 vs 15.4 (Q4) 1.47 (0.80–2.71) 0.26 [31]
Flavanones Naringenin FMC Finnish 30.0 95/5218 0 vs 4.7 (Q4) 1.48 (0.80–2.73) 0.27 [31]
Flavanols CPS-II American 7.8 3974/
43,268
< 10.4 vs
≥ 37.9 (Q5)
1.18 (1.06–1.30) 0.01* 50–74 y; suggestive pos-
itive association for high
grade cancer within the first
2 y of follow-up, not after
excluding these first 2 y;
no associations with ad-
vanced cancer
[16]
Flavanols NLCS Dutch 17.3 3362/
58,279
14.5 vs 98.7 (Q4) 0.97 (0.82–1.15) 0.58 55–69 y; signifi-
cant inverse associa-
tion for stage IV can-
cer [0.73 (0.57–0.95),
p = 0.01*], not for non-ad-
vanced cancer
[33]
Flavanols KIHD Finnish 16.2 138/2590 (Q4) 1.37 (0.65–2.89) 0.82 42–60 y [32]
Flavanols Catechin NLCS Dutch 17.3 3362/
58,279
1.9 vs 6.8 (Q4) 1.03 (0.88–1.22) 0.83 55–69 y; no significant ef-
fect modification by can-
cer stage
[33]
Experimental Oncology 39, 98–105, 2017 (June)39, 98–105, 2017 (June) (June) 101
an inverse association between intake of both genistein
and daidzein and localized cancer [3]. In particular,
Japanese men older than 60 years had about 50%
lower risk of localized prostate cancer with high dietary
consumption of genistein and daidzein [3] (see Table 2).
Thus, compared to findings from case-control studies,
the evidence from prospective cohort studies about the
protective effects of flavonoids against prostate cancer
is much more sparse being restricted to certain sub-
groups (stratified by age of subjects or cancer stage).
Biomarker studies
Unlike the works assessing retrospectively or pro-
spectively dietary intake of different flavonoids, bio-
marker studies have focused only to isoflavones and
their metabolites. At that, no associations were ob-
served between total serum or urinary isoflavones and
prostate cancer risk in English [34] or Scottish men [5].
Null associations were detected also for individual se-
rum isoflavones and their urinary biomarkers (genistein,
daidzein, glycitein, O-desmethylangolensin, equol)
within English men [12, 34] and for serum isoflavones
among older Scottish men [5]. In a large prospective
investigation performed with men from eight European
countries, no significant relationship was reported for
plasma genistein, daidzein or equol and prostate cancer
risk [24, 35]. In the work conducted with Jamaican men,
no association was found between urinary excretion
of genistein or daidzein and prostate cancer incidence,
but a significant inverse relationship was found for uri-
nary equol concentration when non-producers of equol
were assessed as reference group [36]. This study
indicated that men who were able to produce equol
from daidzein by the aid of specific intestinal microflora
were at reduced risk of total and high grade (but not low
Flavonoid
subclass
Certain
compound Stu dya Popula-
tion
Medi-
an fol-
low-up
(years)
Cases/
cohort
Intake comparison
(low vs high,
mg/day)b
Multivariate-
adjusted RR/HRc
p for
trendd Commentse Refe-
rence
Flavanols Epicatechin NLCS Dutch 17.3 3362/
58,279
5.3 vs 20.8 (Q4) 1.01 (0.86–1.20) 0.62 55–69 y; significant in-
verse association for stage
III/IV [0.84 (0.68–1.04),
p = 0.05*] and IV can-
cer [0.74 (0.57–0.95),
p = 0.01*], not for non-ad-
vanced cancer
[33]
Isoflavones CPS-II American 7.8 3974/
43,268
< 0.029 vs
≥ 0.144 (Q5)
1.11 (1.01–1.22) <0.001* 50–74 y; no associations
for high grade or advanced
cancers within or without
the first 2 y of follow-up
[16]
Isoflavones Genistein MEC American,
Hawaiian
8.0 4404/
82,483
< 0.7 vs ≥ 3.1/
1000 kcal (Q5)
0.94 (0.84–1.04) 0.16 45–75 y; multiethnic; no in-
verse association regard-
less of stage
[23]
Isoflavones Genistein JPHC Japanese 5.0 307/
43,509
< 13.2 vs
≥ 32.8 (Q4)
0.71 (0.48–1.03) 0.22 45–74 y; non-significant in-
verse association for lo-
calized, not advanced
cancer; significant in-
verse association for men
> 60 y with localized can-
cer [0.52 (0.30–0.90),
p =0.03*], not advanced
cancer or for younger men
[3]
Isoflavones Daidzein MEC American,
Hawaiian
8.0 4404/
82,483
< 0.7 vs
≥ 3.2/1000 kcal
(Q5)
0.92 (0.82–1.02) 0.09 45–75 y; multiethnic; no in-
verse association regard-
less of stage
[23]
Isoflavones Daidzein JPHC Japanese 5.0 307/
43,509
< 8.5 vs
≥ 20.4 (Q4)
0.77 (0.52–1.13) 0.43 45–74 y; non-significant in-
verse association for lo-
calized, not advanced
cancer; significant in-
verse association for men
> 60 y with localized can-
cer [0.50 (0.28–0.88),
p = 0.04*], not advanced
cancer or for younger men
[3]
Isoflavones Glycitein MEC American,
Hawaiian
8.0 4404/
82,483
< 0.18 vs
≥ 0.80/1000 kcal
(Q5)
0.91 (0.82–1.01) 0.07 45–75 y; multiethnic; no in-
verse association regard-
less of stage
[23]
Anthocyanidins CPS-II American 7.8 3974/
43,268
< 5.9 vs
≥ 18.0 (Q5)
1.10 (1.00–1.22) 0.13 50–74 y; no associations
for high grade or advanced
cancers within or without
the first 2 y of follow-up
[16]
Anthocyanidins KIHD Finnish 16.2 138/2590 (Q4) 0.59 (0.24–1.41) 0.974 42–60 y [32]
Note: aCPS-II — The Cancer Prevention Study II Nutrition Cohort; FMC — The Finnish Mobile Clinic Health Examination Survey; JPHC — The Japan Public
Health Center-based prospective study; KIHD — The Kuopio Ischaemic Heart Disease Risk Factor Study; MEC — The Multiethnic Cohort Study; NLCS — The
Netherlands Cohort Study.
bQ4 — quartiles; Q5 — quintiles.
cRR — relative risk; HR — hazard ratio.
dStatistically significant effects (p for trend < 0.05) are marked by asterisk.
eAge in baseline.
102 Experimental Oncology 39, 98–105, 2017 (June)
Table 3. Epidemiological studies on biomarkers of flavonoids and prostate cancer risk
Flavonoid
subclass
Certain
compound
Bio-
marker Studya Popula-
tion
Cases/
controls
Multivariate-
adjusted OR/RRb
p for
trendc Commentsd Refe-
rence
Isoflavones Serum EPIC-Norfolk English 191/815 1.01 (0.93–1.10) 0.809 45–75 y [34]
Isoflavones Serum PCANDIET Scottish 238/198 1.24 (0.69–2.20) 0.64 50–74 y [5]
Isoflavones Urinary EPIC-Norfolk English 152/665 0.98 (0.90–1.08) 0.727 45–75 y [34]
Isoflavones Genistein Plasma EPIC European 1605/1697 1.00 (0.79–1.27) 0.82 43–76 y; from eight countries; no associations
as stratified by cancer stage (localized or ad-
vanced) or histological grade (low or high),
or age of men at diagnosis (< 60 y or ≥ 60 y)
[35]
Isoflavones Genistein Plasma EPIC European 950/1042 0.74 (0.54–1.00) 0.051* 43–76 y; from eight countries [24]
Isoflavones Genistein Plasma JPHC Japanese 201/402 0.66 (0.40–1.08) 0.08 40–69 y; significant inverse association
for localized cancer [0.54 (0.29–1.01),
p = 0.03*], not advanced cancer
[5]
Isoflavones Genistein Serum JACC Japanese 52/151 0.76 (0.32–1.82) 0.54 ≥ 40 y; suggestive inverse association for
men with T ≥ 6.9 nM, or T ≥ 6.9 nM and PSA
≤ 10 ng/ml for cases, < 4 ng/ml for controls
[25]
Isoflavones Genistein Plasma Chinese 46/54 0.31 (0.13–0.71) 0.006* [4]
Isoflavones Genistein Serum EPIC-Norfolk English 191/815 0.99 (0.93–1.05) 0.78 45–75 y [34]
Isoflavones Genistein Serum EPIC-Norfolk English 89/178 1.01 (0.83–1.23) 0.938 45–75 y [12]
Isoflavones Genistein Serum PCANDIET Scottish 238/198 1.36 (0.76–2.43) 0.37 50–74 y [5]
Isoflavones Genistein Urinary MEC American,
Hawaiian
249/404 0.72 (0.40–1.31) 0.09 45–75 y; multiethnic; suggestive inverse
association for localized and advanced can-
cer, and for Latinos and Whites (not Afri-
can Americans and Japanese Americans)
[37]
Isoflavones Genistein Urinary Jamaican 175/194 1.23 (0.67–2.56) 0.502 40–80 y; no associations as stratified
by cancer grades (low or high)
[36]
Isoflavones Genistein Urinary EPIC-Norfolk English 152/665 1.00 (0.95–1.05) 0.86 45–75 y [34]
Isoflavones Genistein Urinary EPIC-Norfolk English 89/178 0.92 (0.76–1.12) 0.415 45–75 y [12]
Isoflavones Daidzein Plasma EPIC European 950/1042 0.80 (0.60–1.07) 0.209 43–76 y; from eight countries [24]
Isoflavones Daidzein Plasma JPHC Japanese 201/402 0.78 (0.49–1.25) 0.44 40–69 y; suggestive inverse association
for localized, not advanced cancer
[6]
Isoflavones Daidzein Serum EPIC-Norfolk English 89/178 1.01 (0.86–1.18) 0.902 45–75 y [12]
Isoflavones Daidzein Serum EPIC-Norfolk English 191/815 0.99 (0.93–1.05) 0.68 45–75 y [34]
Isoflavones Daidzein Serum PCANDIET Scottish 247/200 1.34 (0.76–2.38) 0.21 50–74 y [5]
Isoflavones Daidzein Serum JACC Japanese 52/151 0.74 (0.31–1.76) 0.50 ≥40 y; suggestive inverse association for
men with T ≥ 6.9 nM, or T ≥ 6.9 nM and PSA
≤ 10 ng/ml for cases, < 4 ng/ml for controls
[25]
Isoflavones Daidzein Urinary MEC American,
Hawaiian
249/404 0.55 (0.31–0.98) 0.03* 45–75 y; multiethnic; suggestive inverse
associations for localized and advanced
cancer, and for different ethnic groups (Af-
rican Americans, Japanese Americans, La-
tinos and Whites)
[37]
Isoflavones Daidzein Urinary Jamaican 175/194 0.85 (0.47–1.54) 0.600 40–80 y; no associations as stratified
by cancer grades (low or high)
[36]
Isoflavones Daidzein Urinary EPIC-Norfolk English 152/665 0.97 (0.92–1.03) 0.31 45–75 y [34]
Isoflavones Daidzein Urinary EPIC-Norfolk English 89/178 0.99 (0.83–1.17) 0.866 45–75 y [12]
Isoflavones Glycitein Plasma JPHC Japanese 201/402 0.78 (0.48–1.26) 0.51 40–69 y; no associations as stratified
by cancer stage (localized or advanced)
[6]
Isoflavones Glycitein Serum EPIC-Norfolk English 191/815 1.01 (0.95–1.08) 0.67 45–75 y [34]
Isoflavones Glycitein Serum EPIC-Norfolk English 89/178 1.08 (0.49–2.38) 0.848 45–75 y [12]
Isoflavones Glycitein Urinary EPIC-Norfolk English 152/665 1.01 (0.96–1.06) 0.81 45–75 y [34]
Isoflavones Glycitein Urinary EPIC-Norfolk English 89/178 1.01 (0.82–1.26) 0.901 45–75 y [12]
Isoflavones O-Des-
methylan-
golensin
Serum EPIC-Norfolk English 191/815 0.97 (0.91–1.03) 0.33 45–75 y [34]
Isoflavones O-Des-
methylan-
golensin
Serum EPIC-Norfolk English 89/178 0.68 (0.36–1.29) 0.236 45–75 y [12]
Isoflavones O-Des-
methylan-
golensin
Urinary EPIC-Norfolk English 152/665 0.98 (0.94–1.03) 0.42 45–75 y [34]
Isoflavones O-Des-
methylan-
golensin
Urinary EPIC-Norfolk English 89/178 0.93 (0.73–1.18) 0.540 45–75 y [12]
Isoflavones Equol Plasma EPIC European 950/1042 0.99 (0.70–1.39) 0.461 43–76 y; from eight countries [24]
Isoflavones Equol Plasma JPHC Japanese 201/402 0.60 (0.36–0.99) 0.04* 40–69 y; significant inverse association
for localized cancer [0.43 (0.22–0.82),
p = 0.02*], not advanced cancer
[6]
Isoflavones Equol Serum EPIC-Norfolk English 191/815 1.02 (0.96–1.08) 0.52 45–75 y [34]
Isoflavones Equol Serum EPIC-Norfolk English 89/178 1.32 (0.73–2.38) 0.358 45–75 y [12]
Isoflavones Equol Serum PCANDIET Scottish 247/200 1.07 (0.71–1.61) 0.75 50–74 y [5]
Isoflavones Equol Serum JACC Japanese 52/151 0.39 (0.15–0.98) 0.046* ≥40 y; suggestive inverse association for
men with T ≥ 6.9 nM, or T ≥ 6.9 nM and PSA
≤ 10 ng/ml for cases, < 4 ng/ml for controls
[25]
Isoflavones Equol Urinary MEC American,
Hawaiian
249/404 1.32 (0.84–2.08) 0.08 45–75 y; multiethnic; no associations
for localized and advanced cancer or dif-
ferent ethnic groups (African Americans,
Japanese Americans, Latinos and Whites)
[37]
Experimental Oncology 39, 98–105, 2017 (June)39, 98–105, 2017 (June) (June) 103
grade) prostate cancer as compared to non-producers
of this metabolite [36]. However, another study that
measured urinary biomarkers of isoflavones did not
observe such protective effect for equol [37]. Quite
contrary, urinary excretion of daidzein was significantly
inversely associated with prostate cancer risk among
multiethnic men living in Hawaii and Los Angeles and
a respective suggestive trend was indicated also for
genistein, regardless of the stage of tumor [37].
Differently from works performed with European and
American men, their Asian counterparts consume sub-
stantially higher amounts of soy foods and consequently
also isoflavones. Wu et al. reported a 69% reduced pros-
tate cancer risk among Chinese men consuming high
amounts of genistein as evaluated by plasma genistein
level [4]. Kurahashi et al. described a significant 44%
reduction in the risk of localized (not advanced) prostate
tumor among Japanese men with higher plasma genis-
tein concentrations and a similar suggestive tendency
was reported also for plasma daidzein level [6]. Plasma
equol level was inversely related to both overall as well
as localized prostate cancer incidence, not modifying
the risk of advanced cancer [6]. A significant 61% de-
crease in prostate cancer risk was detected also in an-
other study with Japanese men with high serum equol
levels and similar suggestive, still non-significant, trend
was observed for genistein and daidzein when the sub-
jects with low serum testosterone levels were excluded
[25]. These studies with Asian men support that high
doses of isoflavones can be indeed preventive against
prostate cancer development (see Table 3).
POTENTIAL FACTORS GIVING RISE
TO INCONCISTENCIES
As come into sight from the epidemiological find-
ings presented in above paragraphs, there are still
relatively few data published about the associations
between flavonoids and prostate cancer risk, and
these results are rather inconclusive. There are seve-
ral potential reasons providing some explanations
to these inconsistencies.
First, assessment of intake of flavonoids has been
limited for a long time due to lack of data about food
composition. Exposure to flavonoids can be estimated
by either food diaries or food frequency questionnaires
and these data are further translated to dietary intake
using quantitative food composition databases [12].
However, reliable information about the content of fla-
vonoids in different plant-derived food items was not
available until the last decade, when several databases
were made public for scientific community [16, 21,
23]. However, these food composition databases are
not able to capture the variability of flavonoid content
attributable to cultivars, growing methods and envi-
ronmental conditions, exposure to sunlight and heat,
or harvesting time and processing practices [21, 33,
38]. Also, these data tables can not detect all sources
of flavonoids in the human diet [37]. Furthermore,
some questions arise by adaptation of food composi-
tion databases created in the US to the diet consumed
in European countries [5, 21].
Second, another possible reason for the incon-
sistent results of epidemiological studies can come
from the differences in level of flavonoids intake. For
example, it has been demonstrated that the mean daily
consumption of isoflavones is low in Western popula-
tions (< 3 mg), whereas it is considerably higher among
Asian subjects reaching even 70–100 mg and being for
most Asian men in the range of 30 to 50 mg [1, 4, 5, 7,
15–17, 23]. Therefore, it can be that the consumption
of isoflavones in Western countries is too low to ob-
serve a protective action against prostate tumor [4,
5, 9, 10, 12, 16, 23, 35]. Whether similar effects exist
also for other flavonoids and their subclasses, i.e. the
risk-lowering response manifests only at a certain
level, is still unknown. The possible age periods of the
highest susceptibility to beneficial effects of flavonoids
have also remained to be determined. Furthermore,
we can not rule out the possibility that follow-up times
of prospective cohort studies were not long enough for
detection of protective action, especially in the case
of advanced neoplasms [16].
Third, it is well known that following to their ingestion,
flavonoids undergo an extensive metabolic conversion
in the intestine and liver, as a result of which various
conjugates with potentially altered biological activity
enter bloodstream and reach target tissues, and are
finally excreted in urine [11, 12]. Blood and urinary bio-
markers can reflect dietary consumption of flavonoids,
capturing intake from all food sources, considering also
their metabolic biotransformation [24, 34]. Therefore,
direct measurement of these biomarkers might provide
a more relevant insight into the associations between
exposure to flavonoids and prostate cancer risk than as-
sessment of food consumption [34]. However, besides
dietary intake, the levels of flavonoids in biological fluids
are affected by intestinal microflora, diet composition
and content of fat in the food, consumption of alcohol,
and the use of antibiotics as well as possible bowel
diseases [5, 28, 36]. Moreover, biomarkers reflect only
Flavonoid
subclass
Certain
compound
Bio-
marker Studya Popula-
tion
Cases/
controls
Multivariate-
adjusted OR/RRb
p for
trendc Commentsd Refe-
rence
Isoflavones Equol Urinary Jamaican 175/194 0.48 (0.26–0.87) 0.020* 40–80 y; significant inverse association
for high grade cancer [0.29 (0.13–0.60),
p = 0.001*], not low grade cancer
[36]
Isoflavones Equol Urinary EPIC-Norfolk English 152/665 1.03 (0.97–1.07) 0.20 45–75 y [34]
Isoflavones Equol Urinary EPIC-Norfolk English 89/178 1.21 (0.93–1.57) 0.147 45–75 y [12]
Note: aEPIC — The European Prospective Investigation into Cancer and Nutrition; JACC — The Japan Collaborative Cohort Study; JPHC — The Japan Public
Health Center-based Prospective Study; MEC — The Multiethnic Cohort Study; PCANDIET — The Prostate Cancer and Diet Study.
bOR — odds ratio; RR — relative risk; the risk for equol is presented in comparison to equol non-producers.
cStatistically significant effects (p for trend < 0.05) are marked by asterisk.
dPSA — prostate-specific antigen; T — testosterone.
104 Experimental Oncology 39, 98–105, 2017 (June)
short-term intake of flavonoids due to their brief half-
lives in the human body and might not accurately reflect
the long-term dietary habits; especially, when only one
serum measurement or spot urine test is used [2, 5, 6,
35–37]. Thus, estimation of dietary intake has remained
indispensable in epidemiological studies, whereas mea-
surement of biomarkers can complement dietary assess-
ment with bioavailability issues. At that, about 30–50%
of people are able to metabolize daidzein to equol, the
most biologically active isoflavone, by the aid of special
intestinal bacteria and this ability varies within different
ethnic populations [8, 9, 19, 36, 38]. Moreover, it has
been shown that the prevalence of equol-producers
is generally lower among subjects suffering from prostate
cancer compared to healthy controls [2, 8, 19]. For ex-
ample, it was shown that just 29% of Japanese men with
prostate cancer could produce equol, compared to 46%
of controls and these estimates were 30% and 59% for
Korean cases and controls, respectively [8]. If further
studies confirm that equol can lower the prostate cancer
risk and intestinal environment without equol-converting
bacteria is indeed a risk factor for this malignancy, a pos-
sible prevention strategy for future would be to improve
intestinal microflora by probiotic technology, enabling
it to generate equol [7, 9].
In the case of retrospective study design, the recall
bias is unavoidable. Patients could recall their food
consumption differently than controls and it is also
possible that they changed their diet after cancer was
diagnosed [15, 21]. However, this misclassification
was probably non-differential, as the knowledge about
possible role of flavonoids on prostate carcinogenesis
was not widespread among general public [15, 28].
Analysis of data collected prospectively might reduce
the problems of disease-related influences on dietary
intake of flavonoid-rich food items or their biomarker
levels [34, 37]. However, the number of cases could
not be large enough for acceptably strong statistical
power, especially for subgroup analyses stratified
by different parameters [19, 33, 37].
Another common concern in epidemiological studies
is potential confounding. Despite adjustment for diverse
aspects, it is always possible that residual confounders
due to uncontrolled or as yet unknown factors might re-
main [5, 12, 15, 16, 26, 27, 36]. For example, most of the
studies did not collect information about testing of pros-
tate specific antigen that might be a confounder [16,
33]. Also, only few investigations considered histological
grade or tumor stage, although risk factors of prostate
cancer can vary within subgroups differentiated by di-
sease aggressiveness or stage [8, 26, 33]. In addition,
lifestyle related to consumption of higher doses of fla-
vonoids or some dietary covariates might contribute
to the susceptibility to prostate carcinogenesis [3, 5,
10, 16]. Furthermore, Hedelin et al. indicated that health
benefits of isoflavone intake against prostate tumor can
be restricted to men carrying specific genetic variant
in estrogen receptor β gene [28].
CONCLUSIONS AND FURTHER
PERSPECTIVES
High incidence rate, slow progression and long
course make prostate cancer a perfect disorder for
chemoprevention which onset, development and pro-
gression can be influenced by certain dietary constitu-
ents [20]. There are several epidemiological findings
suggesting that high intake of specific flavonoids can
lead to reduced prostate cancer risk. Indeed, consump-
tion of isoflavones at doses characteristic to Asian
population may modulate the risk of prostate cancer
and therefore, high intake of these phytoestrogens
might be an efficient protective means against prostate
tumorigenesis among Chinese and Japanese men. The
stronger preventive effect of isoflavones on localized
tumor compared to advanced neoplasm is in agreement
with the expression of estrogen receptor β in normal
prostate tissue and early stages neoplasm, decline
in expression during malignant transformation and com-
plete loss in advanced tumor with higher metastatic po-
tential and mortality; supposing that preventive effects
of isoflavones are mediated via this receptor subtype [3,
6, 28]. Based on the autopsy studies the rate of latent
tumors is similar in Asian and Western countries and
the significantly lower incidence of clinically detectable
prostate tumors in Asian men can come from blocking
and delaying the latent cancer progression by intake
of high amounts of isoflavones [3, 6]. An important
factor in health benefits of high consumption of isofla-
vones seems to arise also from the ability to metabolize
daidzein to equol by possessing a specific intestinal
bacterial combination. Whether ethnic variation in this
metabolic conversion may provide some explana-
tion to the differences in prostate cancer incidence
remains to be further clarified. On the other hand,
some epidemiological studies with Western men have
demonstrated the protective action of certain flavonols
or flavanols manifesting particularly against advanced,
later stage tumor. As a whole, these data indicate that
through intake of various plant-derived phytochemicals
nature can provide protection and chemoprevention
against different stages of prostate cancer.
There is no doubt that large-scale and preferentially
prospectively designed studies are needed to further
investigate the association between exposure to fla-
vonoids and the risk of prostate cancer. At that, sub-
jects with consumption of wider concentration range
of these plant metabolites as well as stratification
by different factors, including disease stage, are highly
needed. If the protective effects will be confirmed,
chemopreventive intervention strategies via modifica-
tion of dietary habits can be developed to reduce the
prostate cancer incidence, especially among at-risk
men. Last but not least, although adverse effects
of flavonoids on the prostate tissue have not been
reported, studies considering safety profile of these
phytochemicals are never too much.
CONFLICT OF INTEREST
None declare.
Experimental Oncology 39, 98–105, 2017 (June)39, 98–105, 2017 (June) (June) 105
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| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Sak, K. 2018-06-17T14:18:01Z 2018-06-17T14:18:01Z 2017 Current epidemiological knowledge about the role of flavonoids in prostate carcinogenesis / K. Sak // Experimental Oncology. — 2017 — Т. 39, № 2. — С. 98–105. — Бібліогр.: 38 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/137628 Numerous experimental studies have demonstrated anticancer action of polyphenolic plant metabolites. However, data about associations between dietary intake of plant-derived flavonoids and prostate cancer risk are still sparse and inconsistent. This minireview compiles the epidemiological findings published to date on the role of flavonoids in prostate tumorigenesis, discusses the reasons of inconsistencies and elicits the promising results for chemoprevention of this malignancy. Long-term consumption of high doses of soy isoflavones can be the reason of markedly lower clinically detectable prostate cancer incidence among Asian men compared to their counterparts in the Western world. The ability to metabolize daidzein to equol, the most biologically active isoflavone, by the certain intestinal bacteria also seems to contribute to this important health benefit. The increasing incidence rate of prostate cancer related to adoption of westernized lifestyle and dietary habits makes the issue of chemoprevention ever more important and directs the eyes to specific food components in the Eastern diet. If further large-scale epidemiological studies will confirm the protective effects of isoflavones against prostate cancer, this could provide an important way for prostate cancer prevention, as diet is a potentially modifiable factor in our behavioral pattern. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Reviews Current epidemiological knowledge about the role of flavonoids in prostate carcinogenesis Article published earlier |
| spellingShingle | Current epidemiological knowledge about the role of flavonoids in prostate carcinogenesis Sak, K. Reviews |
| title | Current epidemiological knowledge about the role of flavonoids in prostate carcinogenesis |
| title_full | Current epidemiological knowledge about the role of flavonoids in prostate carcinogenesis |
| title_fullStr | Current epidemiological knowledge about the role of flavonoids in prostate carcinogenesis |
| title_full_unstemmed | Current epidemiological knowledge about the role of flavonoids in prostate carcinogenesis |
| title_short | Current epidemiological knowledge about the role of flavonoids in prostate carcinogenesis |
| title_sort | current epidemiological knowledge about the role of flavonoids in prostate carcinogenesis |
| topic | Reviews |
| topic_facet | Reviews |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/137628 |
| work_keys_str_mv | AT sakk currentepidemiologicalknowledgeabouttheroleofflavonoidsinprostatecarcinogenesis |