Article

Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg)

Division of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
American Journal of Clinical Nutrition (Impact Factor: 6.77). 05/2008; 87(4):985-92.
Source: PubMed

ABSTRACT

Anticarcinogenic activities of vitamin K have been observed in various cancer cell lines, including prostate cancer cells. Epidemiologic studies linking dietary intake of vitamin K with the development of prostate cancer have not yet been conducted.
We evaluated the association between dietary intake of phylloquinone (vitamin K1) and menaquinones (vitamin K2) and total and advanced prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition.
At baseline, habitual dietary intake was assessed by means of a food-frequency questionnaire. Dietary intake of phylloquinone and menaquinones (MK-4-14) was estimated by using previously published HPLC-based food-content data. Multivariate-adjusted relative risks of total and advanced prostate cancer in relation to intakes of phylloquinone and menaquinones were calculated in 11 319 men by means of Cox proportional hazards regression.
During a mean follow-up time of 8.6 y, 268 incident cases of prostate cancer, including 113 advanced cases, were identified. We observed a nonsignificant inverse association between total prostate cancer and total menaquinone intake [multivariate relative risk (highest compared with lowest quartile): 0.65; 95% CI: 0.39, 1.06]. The association was stronger for advanced prostate cancer (0.37; 0.16, 0.88; P for trend = 0.03). Menaquinones from dairy products had a stronger inverse association with advanced prostate cancer than did menaquinones from meat. Phylloquinone intake was unrelated to prostate cancer incidence (1.02; 0.70, 1.48).
Our results suggest an inverse association between the intake of menaquinones, but not that of phylloquinone, and prostate cancer. Further studies of dietary vitamin K and prostate cancer are warranted.

Full-text

Available from: Sabine Rohrmann
Dietary intake of vitamin K and risk of prostate cancer in the
Heidelberg cohort of the European Prospective Investigation into
Cancer and Nutrition (EPIC-Heidelberg)
1–3
Katharina Nimptsch, Sabine Rohrmann, and Jakob Linseisen
ABSTRACT
Background: Anticarcinogenic activities of vitamin K have been
observed in various cancer cell lines, including prostate cancer cells.
Epidemiologic studies linking dietary intake of vitamin K with the
development of prostate cancer have not yet been conducted.
Objective: We evaluated the association between dietary intake of
phylloquinone (vitamin K1) and menaquinones (vitamin K2) and
total and advanced prostate cancer in the Heidelberg cohort of the
European Prospective Investigation into Cancer and Nutrition.
Design: At baseline, habitual dietary intake was assessed by means
of a food-frequency questionnaire. Dietary intake of phylloquinone
and menaquinones (MK-4–14) was estimated by using previously
published HPLC-based food-content data. Multivariate-adjusted
relative risks of total and advanced prostate cancer in relation to
intakes of phylloquinone and menaquinones were calculated in
11 319 men by means of Cox proportional hazards regression.
Results: During a mean follow-up time of 8.6 y, 268 incident cases
of prostate cancer, including 113 advanced cases, were identified.
We observed a nonsignificant inverse association between total
prostate cancer and total menaquinone intake [multivariate relative
risk (highest compared with lowest quartile): 0.65; 95% CI: 0.39,
1.06]. The association was stronger for advanced prostate cancer
(0.37; 0.16, 0.88; P for trend ҃ 0.03). Menaquinones from dairy
products had a stronger inverse association with advanced prostate
cancer than did menaquinones from meat. Phylloquinone intake was
unrelated to prostate cancer incidence (1.02; 0.70, 1.48).
Conclusions: Our results suggest an inverse association between the
intake of menaquinones, but not that of phylloquinone, and prostate
cancer. Further studies of dietary vitamin K and prostate cancer are
warranted. Am J Clin Nutr 2008;87:985–92.
INTRODUCTION
Fat-soluble vitamin K evolves its essential function as a co-
factor for the posttranslational
-carboxylation of glutamate res-
idues in vitamin K– dependent proteins (1). The term vitamin K
refers to a group of compounds that have a 2-methyl-1,4-
naphtoquinone ring in common but that differ in the length and
structure of their isoprenoid side chain at the 3-position. The 2
forms of vitamin K that occur naturally in foods are phylloqui-
none (vitamin K
1
) and the group of menaquinones (vitamin K
2
,
MK-n), which vary in the number of prenyl units. Whereas phyl-
loquinone is abundant in green leafy vegetables and some veg-
etable oils, menaquinones are synthesized by bacteria; therefore,
they mainly occur in fermented products such as cheese. Meat
and meat products also form a relevant source of menaquinones,
especially MK-4, which is synthesized in the animals from either
phylloquinone or the synthetic menadione (vitamin K
3
) com
-
monly added to animal foods (2). Because of the quinone struc-
ture, which poses as functional unit of several chemotherapeutics
in cancer therapy, vitamin K has gained importance in the pre-
vention and treatment of cancer (3). The synthetic menadione
(vitamin K
3
) inhibits carcinogenic cell growth, especially in
combination with vitamin C, by oxidative processes leading to
oxidative stress and depletion of cellular thiols (4, 5). Phylloqui-
none and menaquinones exert growth-inhibitory effects on can-
cer cells by acting as transcription factors of proto-oncogenes
such as c-myc, c-fos,orc-jun, which foster cell-cycle arrest and
apoptosis (6, 7). Antitumor activities of phylloquinone and
menaquinones have been observed in various cancer cell lines,
including liver, lung, stomach, and breast (5–11); in the case of
menaquinones, several studies worked with MK-4 (5, 7–9) and
one study worked with MK-1–3 (10), whereas others did not
specify the type (6, 11). In a randomized trial of 43 women with
viral cirrhosis of the liver, mega-doses of menaquinones (45
mg/d; type not specified) decreased the risk of hepatocellular
carcinoma by 80% compared with the control group (12). Con-
cerning prostate cancer, menadione has been shown to reduce
tumor growth rate in vitro (13) and in vivo (14), whereas K
vitamins naturally occurring in the human diet were not investi-
gated. To the best of our knowledge, epidemiologic studies link-
ing the dietary intake of vitamin K with the development of
prostate cancer have not been conducted so far. Here, we exam-
ine the hypothesis that dietary vitamin K intake is inversely
associated with the incidence of prostate cancer in a prospective
cohort study.
1
From the Division of Cancer Epidemiology, German Cancer Research
Centre, Heidelberg, Germany.
2
Supported by contract no. 513943 from Environmental Cancer Risk,
Nutrition and Individual Susceptibility (ECNIS), a network of excellence
operating within the European Union’s 6th Framework Program, Priority 5,
“Food Quality and Safety,” and by Graduiertenkolleg 793 scholarship from
the Deutsche Forschungsgemeinschaft (to KN).
3
Reprints not available. Address correspondence to J Linseisen, German
Cancer Research Center, Division of Cancer Epidemiology, Unit of Nutri-
tional Epidemiology, Im Neuenheimer Feld 280, DE-69120 Heidelberg, Ger-
many. E-mail: j.linseisen@dkfz-heidelberg.de.
Received August 23, 2007.
Accepted for publication October 25, 2007.
985Am J Clin Nutr 2008;87:985–92. Printed in USA. © 2008 American Society for Nutrition
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SUBJECTS AND METHODS
Study population
The Heidelberg cohort of the European Prospective Investi-
gation into Cancer and Nutrition (EPIC-Heidelberg) comprises
25 540 participants, of whom 11 928 are men aged 40 65 y.
Recruitment from a random sample of the general population
from Heidelberg and surrounding communities took place be-
tween June 1994 and October 1998, and the overall participation
rate of invited subjects was 38.3% (15). At baseline, information
on dietary and nondietary factors was assessed by self-
administered questionnaires and a personal interview including
questions on marital status, education, occupational status,
smoking history, physical activity, use of medication, and history
of disease. Anthropometric measurements including partici-
pant’s weight and height were taken in the study center by trained
interviewers following standardized methods. Follow-up was
performed actively by mailed follow-up questionnaires ascer-
taining new cases of various diseases. The response rates in the
3 follow-up rounds completed to date were 93.5% (1st follow-up,
1998 –2000), 91.8% (2nd follow-up, 2001–2004), and 92.0%
(3rd follow-up, 2004 –2007). The second and third follow-ups
included questions on participation in prostate-specific antigen
(PSA)-screening tests.
All participants gave written informed consent. The study was
approved by the ethics committee of the Heidelberg Medical
School.
Dietary data
Habitual dietary intake during the previous 12 mo was as-
sessed by using a 145-item semi-quantitative food-frequency
questionnaire (FFQ) at baseline. For each food item, participants
specified typical portion size and consumption frequency, rang-
ing from 1 time/mo to 6 times/d (16). Average daily food intake
was calculated from the information on portion size and fre-
quency of consumption for each food item. Calculation of the
intakes of individual nutrients was carried out by using the Ger-
man Food and Nutrition Database (BLS 2.3) (17). In this table,
however, food content data on vitamin K is insufficient because
the data sources are not exclusively based on HPLC-measured
values, which are considered as the most reliable, and no data on
menaquinones (vitamin K
2
) are provided. Therefore, dietary in
-
takes of phylloquinone and menaquinones were calculated by
using previously published food content data based exclusively
on HPLC. For the calculation of phylloquinone intake, data
[(18); also: C Bolton-Smith et al, unpublished observations,
2000] that included values for 2000 foods were applied. The
menaquinone (MK-4 –14) content of relevant foods was derived
from a Dutch publication (19) and supplemented with Japanese
data on offal (20). Phylloquinone and menaquinone contents
were assigned to the single foods contributing to the FFQ items
either by direct matching, with adjustment for fat content where
necessary (as described by Bolton-Smith et al), or on the basis of
food similarities. Whereas some convenience products or mixed
dishes, such as soups and cakes, are listed with their phylloqui-
none content in the database by Bolton-Smith et al, the phyllo-
quinone content of some other combined foods consumed in
EPIC-Heidelberg was calculated by means of standard recipes.
Calculation of the menaquinone contents in “mixed” food,
mainly cakes, was performed by recipe calculation.
Identification of prostate cancer cases
Identification of incident prostate cancer cases was based on
self-reported primary prostate cancer during follow-up or on
death certificates that were coded for prostate cancer as the un-
derlying cause of death. All identified cases of incident prostate
cancer— except the 8 most recent cases—were verified by med-
ical records, death certificates, or both. Because of the high
sensitivity of self-reports of prostate cancer as observed among
the verified cases, the 8 cases based only on self-reports were
included in the analysis. Information on stage and grade of pros-
tate cancer was extracted by the study physician from pathology
reports (procedures or tests conducted during the initial diagno-
sis), including tumor nodal metastasis (TNM) stage, Gleason
histologic grade, and PSA level. Advanced prostate cancer was
defined as prostate cancer with a Gleason sum score of 7; TNM
staging score of T3/T4, N1-N3, or M1; PSA level at diagnosis of
20 ng/mL; or prostate cancer as the underlying cause of death.
Although prone to detection bias, stage T1a cases were included
in the analysis because their low number (n ҃ 4, 2% of all
cases) was unlikely to affect the results.
Statistical analyses
The analytic cohort comprised 11 319 men after exclusion of
subjects with missing dietary information or prevalent cancer
(except for nonmelanoma skin cancer) (n ҃ 955) and those in the
top and bottom 1% of energy intake (ie, 981 or 4815 kcal; n
҃ 230). Individual person-time was calculated from the date of
recruitment and the date of diagnosis of prostate cancer, the date
of death from other causes, or the date of the last known contact,
whichever came first.
The association between intakes of phylloquinone and total
menaquinones (sum of MK-4 to MK-14) and the risk of total and
advanced prostate cancer was analyzed by using Cox propor-
tional hazards regression, calculating relative risks (RRs) (and
95% CIs). For both total and advanced prostate cancer, analyses
were repeated after exclusion of cases diagnosed within the first
2 y after recruitment.
For the analyses, dietary intakes of phylloquinone and mena-
quinones were categorized into quartiles and entered simulta-
neously into the models. Tests for linear trends (P for trend) were
performed by modeling the median values of phylloquinone and
menaquinone quartiles as continuous variables. In addition, con-
tinuous models for intakes of phylloquinone and menaquinones
were calculated per 10-
g increment. All models were stratified
by age (in 1-y categories). Multivariate analyses were adjusted
for potential confounders, including smoking status [never
smokers, current cigarette smokers (1–14 or 15 cigarettes/d),
former smokers who stopped 10 or 10 y ago, or other smok-
ers (pipe or cigar smokers or occasional smokers)], education
(none or primary school, technical school, secondary school, or
university degree), vigorous physical activity (none, 2 h/wk, or
2 h/wk), energy from fat (kcal/d, in quartiles), nonfat-
nonalcohol energy (kcal/d, in quartiles), alcohol (4.9, 5–14.9,
15–30, or 30 g ethanol/d), calcium (mg/d, in quartiles), vitamin
D (IU/d, in quartiles), tomato or tomato products (g/d, in quar-
tiles), body mass index (in kg/m
2
, continuous), history of diabe
-
tes, and family history of prostate cancer. Other dietary and
nondietary factors were examined but not included in the model
when they neither were associated with prostate cancer nor con-
founded the association of vitamin K intake with prostate cancer.
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Multivariate analyses were repeated with additional adjustment
for consumption of vegetables, dairy products (including milk,
cheese, and other dairy products), and meat (g/d, in quartiles). In
a second approach, the intakes of menaquinones from major food
sources (dairy products and meat or meat products) were mod-
eled separately as continuous variables, after adjustment for
phylloquinone and menaquinones from other sources in the mul-
tivariate model. Finally, menaquinones were modeled separately
according to the length of the isoprenoid side chain (MK-4 com-
pared with MK-5–9, continuous). All statistical analyses were
performed with SAS software (version 9.1; SAS Institute, Cary,
NC).
RESULTS
During a mean follow-up time of 8.6 y (97 731 total person-
years), 268 incident cases of prostate cancer occurred, including
113 advanced cases (42% of all cases). Thirty-six cases (13% of
all cases) were diagnosed during the first2yoffollow-up. Me-
dian (25–75th percentile) intakes of phylloquinone and total
menaquinones (MK-4–14) were 93.6 (70.9–123.5) and 34.7
(25.7– 45.7)
g/d, respectively (Table 1).
Dietary phylloquinone was mainly provided by vegetables,
soups or bouillon, fruit, and cereals or cereal products. Green
leafy vegetables, including spinach, all varieties of lettuce, cab-
bage, Brussels sprouts, and broccoli, contributed 42% of phyl-
loquinone intake. The main contributors of menaquinones were
dairy products, meat or meat products, and cakes. Cheese was the
greatest single food source, contributing 43% of total intake of
menaquinones. The relatively high contributions of soups or
bouillon to phylloquinone intake and of cakes to menaquinone
intake can be explained by the vitamin K content of some ingre-
dients. Such ingredients include vegetable oils and vegetables,
which contribute to the phylloquinone content of soups or bouil-
lon, and eggs and dairy products (eg, butter and cream), which
contribute to the menaquinone content of cakes. The subgroups
of menaquinones differed with respect to food sources. Whereas
the main food source of MK-4 (median intake 14.4
g/d) was
meat or meat products (37% of total intake), higher menaquino-
nes MK-5–9 (median intake: 18.0
g/d) were almost exclusively
(85% of total intake) derived from dairy products. Menaquinones
above MK-9 contributed little to total menaquinone intake (me-
dian intake: 0.8
g/d) and were provided to 86% by meat or meat
products, especially offal.
The upper quartiles of phylloquinone intake were associated
with greater age, whereas the upper quartiles of intake of mena-
quinones were associated with lower age (Table 2). Subjects in
the upper quartiles of phylloquinone and menaquinones had a
lower body mass index, were more likely to have a university
degree, and were more likely to practice vigorous physical ac-
tivity 2 h/wk than were subjects in the lower intake quartiles.
The smoking status of the participants did not differ distinctly
between quartiles of vitamin K intake. A history of diabetes was
more common in subjects in the upper quartiles of phylloquinone
and less common in those in the upper quartiles of menaquinones.
Participation in PSA screening was more common in subjects in
the upper quartiles of phylloquinone (but not menaquinone) in-
take. A family history of prostate cancer was not associated with
intake of phylloquinone or menaquinones. Total energy intake
increased across quartiles of phylloquinone and menaquinones.
Consequently, dietary intake of other energy-related nutrients
and food groups increased by quartiles.
As shown in Table 3, dietary intake of phylloquinone was not
associated with the incidence of either total or advanced prostate
cancer. However, intake of menaquinones was nonsignificantly
and inversely related to the risk of total prostate cancer (P for
TABLE 1
Median intakes of dietary phylloquinone and menaquinones and the main contribution of food group consumption to total intake in EPIC-Heidelberg
1
Intake Sources: food group and subgroup
Total intake of the
specific nutrient
g/d %
Phylloquinone 93.6 (70.9–123.5)
2
Vegetables 62
Green leafy vegetables 42
Soups, bouillon 6
Fruits 6
Cereals, cereal products 5
Sum of menaquinones (MK-4–14) 34.7 (25.7–45.7)
Dairy products 60
Cheese 43
Meat, meat products 17
Cakes 7
MK-4 14.4 (10.9–18.7) Meat, meat products 37
Dairy products 16
Cakes 14
Egg, egg products 11
MK-5–9
3
18.0 (11.7–27.0) Dairy products 85
MK-10–14
3
0.8 (0.2–1.7) Meat, meat products 86
Offal 67
1
n ҃ 11 319. EPIC, European Prospective Investigation into Cancer and Nutrition.
2
Median; interquartile range in parentheses (all such values).
3
Individual menaquinone intakes: MK-5, 0.3 (0.2– 0.5); MK-6, 0.3 (0.2– 0.5); MK-7, 0.8 (0.5–1.1); MK-8, 4.6 (3.1– 6.7); MK-9, 11.9 (7.4 –18.4); MK-10,
0.06 (0.01– 0.13); MK-11, 0.12 (0.03– 0.27); MK-12, 0.20 (0.04 0.42); MK-13, 0.40 (0.08 0.85); and MK-14, 0.02 (0.00 0.05)
g/d.
VITAMIN K INTAKE AND RISK OF PROSTATE CANCER 987
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TABLE 2
Baseline characteristics of men of the EPIC-Heidelberg cohort by quartile (Q) of phylloquinone and menaquinone intake
1
Baseline characteristics
Phylloquinone (
g/d) Menaquinones (
g/d)
2
Q1
(71)
Q2
(71–94)
Q3
(94 –124)
Q4
(124)
P for
trend
3
Q1
(26)
Q2
(26 –35)
Q3
(35– 46)
Q4
(46)
P for
trend
3
Age at baseline (y) 51.4 7.0
4
52.0 7.1 52.1 7.1 52.3 7.1 0.0001 53.4 6.9 52.0 7.1 51.8 7.1 50.6 7.1 0.0001
BMI (kg/m
2
)
27.1 3.5 27.0 3.6 27.0 3.6 26.8 3.9 0.01 27.1 3.5 27.0 3.7 26.9 3.5 26.8 3.9 0.001
Body weight (kg) 83.4 11.7 83.4 12.1 83.7 12.0 83.3 12.8 0.65 82.8 11.5 83.4 12.1 83.7 11.8 84.0 13.0 0.002
Body height (cm) 175 6.5 176 6.7 176 6.7 176 6.8 0.0001 175 6.5 176 6.5 176 6.7 177 6.9 0.0001
Educational level (%)
None or primary
school
35 30 31 29 37 32 30 26
Technical school 28 29 27 24 30 29 25 23
Secondary school 5 6 6 6 5557
University degree 32 36 37 41 0.0001 29 34 40 44 0.0001
Smoking status (%)
Never 29 31 31 30 29 31 31 29
Former 43 45 44 44 47 43 44 43
Current 28 24 25 26 0.07 24 27 25 28 0.14
Vigorous physical
activity (%)
None 37 37 34 34 39 36 33 33
2 h/wk 38 37 39 35 36 37 39 37
2 h/wk 25 26 28 31 0.0001 26 27 28 29 0.0001
History of diabetes (%) 4 5 5 6 0.002 65540.001
PSA screening (%) 46 49 49 49 0.02 49 49 49 46 0.08
Family history of prostate
cancer (%)
4 4 3 3 0.55 34430.58
Nutrient intake
Total energy (kcal/d) 1889 528 2106 555 2286 631 2513 728 0.0001 1724 423 2047 476 2294 537 2729 703 0.0001
Total fat (g/d) 68.5 23.5 78.5 25.7 87.2 29.8 98.7 35.5 0.0001 57.6 15.2 74.3 18.1 88.2 23.4 112.7 33.6 0.0001
Alcohol (ethanol, g/d) 26.6 28.3 25.1 24.6 25.6 26.1 26.0 27.3 0.16 25.6 26.9 26.2 27.3 26.1 26.8 25.3 25.5 0.55
Calcium (mg/d) 676 324 750 315 821 355 914 383 0.0000 550 204 692 241 827 283 1093 410 0.0001
Phosphor (mg/d) 1166 352 1302 360 1422 406 1572 465 0.0001 1055 275 1254 300 1421 328 1732 452 0.0001
Vitamin D (IU/d) 122.0 86.5 137.7 82.6 153.8 114.4 181.5 147.3 0.0001 110.1 80.0 137.6 91.1 154.2 99.2 193.1 151.3 0.0001
Food intake (g/d)
Vegetables 70.4 26.4 98.8 27.9 116.9 35.6 161.9 67.7 0.0001 98.8 48.8 107.6 49.3 114.9 50.2 126.9 63.2 0.0001
Green leafy vegetables 12.1 6.5 20.7 8.5 26.8 10.9 42.1 22.4 0.0001 23.5 16.1 24.8 16.1 26.0 16.6 27.5 20.3 0.0001
Dairy products 209.3 228.3 219.0 207.7 245.5 240.7 263.9 249.7 0.0001 158.3 148.7 205.5 189.0 250.3 228.9 323.6 303.9 0.0001
Cheese 25.6 20.1 28.3 20.9 30.0 22.2 33.7 25.8 0.0001 12.4 7.3 21.1 10.0 30.7 12.1 53.4 28.2 0.0001
Meat, meat products 105.8 61.7 117.2 64.6 124.6 71.3 138.9 86.9 0.0001 89.1 45.8 111.6 55.7 128.2 66.7 157.5 95.1 0.0001
Tomatoes, tomato
products
18.7 11.7 22.6 12.7 24.7 15.2 29.3 18.2 0.0001 18.8 13.4 23.1 13.6 24.7 13.9 28.6 17.5 0.0001
1
EPIC, European Prospective Investigation into Cancer and Nutrition; PSA, prostate-specific antigen.
2
The sum of menaquinones MK-4 to MK-14.
3
Likelihood ratio test or Jonckheere-Terpstra test.
4
x SD (all such values).
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TABLE 3
Phylloquinone and menaquinone intakes and the relative risk (RR) of prostate cancer in men of the EPIC-Heidelberg cohort
1
Phylloquinone (
g/d) Menaquinones (
g/d)
2
Q1
(71)
Q2
(71–94)
Q3
(94 –124)
Q4
(124)
P for
trend Continuous RR
3
Q1
(26)
Q2
(26 –35)
Q3
(35– 46)
Q4
(46)
P for
trend Continuous RR
3
Total prostate cancer
Cases (n)6664 6573 91656250
Age-stratified RR 1.00 0.94 (0.66, 1.33)
4
0.97 (0.69, 1.38) 1.09 (0.77, 1.54) 0.55 1.00 (0.98, 1.03) 1.00 0.81 (0.59, 1.11) 0.79 (0.57, 1.10) 0.73 (0.51, 1.04) 0.09 0.95 (0.88, 1.03)
Multivariate RR
5
1.00 0.88 (0.62, 1.25) 0.91 (0.63, 1.31) 1.02 (0.70, 1.48) 0.74 1.00 (0.98, 1.03) 1.00 0.76 (0.53, 1.08) 0.71 (0.47, 1.06) 0.65 (0.39, 1.06) 0.10 0.94 (0.84, 1.05)
Multivariate RR
6
1.00 0.85 (0.59, 1.25) 0.90 (0.60, 1.36) 1.02 (0.64, 1.61) 0.72 1.00 (0.97, 1.03) 1.00 0.75 (0.52, 1.07) 0.68 (0.45, 1.04) 0.61 (0.36, 1.02) 0.07 0.93 (0.82, 1.04)
Total prostate cancer,
excluding cases
occuring in the
first 2 y after
recruitment
Cases 56 55 55 66 79 54 54 45
Age-stratified RR 1.00 0.96 (0.66, 1.40) 0.99 (0.68, 1.44) 1.17 (0.81, 1.70) 0.34 1.01 (0.98, 1.03) 1.00 0.76 (0.53, 1.07) 0.78 (0.55, 1.10) 0.73 (0.50, 1.07) 0.12 0.96 (0.88, 1.04)
Multivariate RR
5
1.00 0.91 (0.62, 1.33) 0.92 (0.62, 1.37) 1.09 (0.73, 1.62) 0.53 1.00 (0.98, 1.03) 1.00 0.69 (0.47, 1.01) 0.66 (0.43, 1.02) 0.61 (0.36, 1.04) 0.10 0.94 (0.84, 1.06)
Multivariate RR
6
1.00 0.86 (0.57, 1.29) 0.87 (0.56, 1.36) 1.02 (0.62, 1.66) 0.74 1.00 (0.97, 1.03) 1.00 0.68 (0.46, 1.00) 0.64(0.41, 0.99) 0.57 (0.33, 0.98) 0.06 0.93 (0.82, 1.06)
Advanced prostate
cancer
Cases 27 33 28 25 42 29 27 15
Age-stratified RR 1.00 1.19 (0.71, 1.99) 1.04 (0.61, 1.77) 0.98 (0.56, 1.70) 0.76 1.00 (0.96, 1.04) 1.00 0.79 (0.49, 1.28) 0.76 (0.47, 1.25) 0.51 (0.28, 0.93) 0.03 0.87 (0.76, 0.99)
Multivariate RR
5
1.00 1.11 (0.66, 1.88) 0.97 (0.56, 1.71) 0.84 (0.46, 1.56) 0.50 0.99 (0.95, 1.03) 1.00 0.79 (0.47, 1.34) 0.67 (0.36, 1.25) 0.37 (0.16, 0.88) 0.03 0.81 (0.67, 0.99)
Multivariate RR
6
1.00 1.18 (0.67, 2.06) 1.11 (0.59, 2.08) 1.09 (0.52, 2.27) 0.93 1.01 (0.96, 1.06) 1.00 0.77 (0.45, 1.31) 0.63 (0.33, 1.19) 0.33 (0.14, 0.80) 0.01 0.76 (0.61, 0.95)
Advanced prostate
cancer, excluding
cases occuring in
the first 2 y after
recruitment
Cases 22 26 21 20 34 20 22 13
Age-stratified RR 1.00 1.16 (0.66, 2.06) 0.97 (0.53, 1.78) 0.96 (0.52, 1.79) 0.73 1.00 (0.95, 1.04) 1.00 0.66 (0.38, 1.16) 0.75 (0.44, 1.30) 0.53 (0.27, 1.01) 0.07 0.89 (0.77, 1.04)
Multivariate RR
5
1.00 1.12 (0.62, 2.03) 0.92 (0.49, 1.74) 0.85 (0.43, 1.68) 0.49 0.99 (0.94, 1.04) 1.00 0.62 (0.33, 1.14) 0.60 (0.30, 1.21) 0.34 (0.13, 0.86) 0.03 0.82 (0.65, 1.03)
Multivariate RR
6
1.00 1.16 (0.62, 2.19) 0.96 (0.47, 1.97) 0.94 (0.41, 2.17) 0.74 1.00 (0.94, 1.06) 1.00 0.61 (0.33, 1.13) 0.57 (0.28, 1.16) 0.29 (0.11, 0.76) 0.02 0.79 (0.62, 1.00)
1
n ҃ 11 319. EPIC, European Prospective Investigation into Cancer and Nutrition; Q, quartile.
2
Sum of menaquinones MK-4 to MK-14.
3
Per 10-
g/d increment.
4
RR; 95% CIs in parentheses (all such values).
5
Cox proportional hazards models, adjusted for smoking (never, quit 10 y ago, quit 10 y ago, current 15 cigarettes/d, current 15 cigarettes/d, or other smoking), education (none or primary school,
technical school, secondary school, or university degree), vigorous physical activity (none, 2 h/wk, or 2h/wk), energy from fat, alcohol, nonfat-nonalcohol energy, calcium, vitamin D, tomato or tomato products
(all nutrients entered as quartile-dummies), BMI, history of diabetes, and family history of prostate cancer.
6
Cox proportional hazards models as in footnote 5, with additional adjustment for the intake of vegetables, dairy products, and meat or meat products (quartiles).
VITAMIN K INTAKE AND RISK OF PROSTATE CANCER 989
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trend ҃ 0.06), showing significantly reduced RRs in the 3rd and
4th quartiles after exclusion of cases diagnosed within the first 2 y
of follow-up and after further adjustment for food group intake.
For advanced prostate cancer, the inverse relation with intake of
menaquinones was even stronger and statistically significant in
the multivariate-adjusted models. When advanced prostate can-
cer was alternatively defined separately according to stage (TNM
stage T3/T4, N1–N3, or M1; n ҃ 50) or grade (Gleason sum score
7; n ҃ 74), obtained risk estimates were similar to those of the
combined definition of advanced prostate cancer, but they were
not significant, because of the low number of cases (data not
shown). The multivariate adjustment and exclusion of cases di-
agnosed within the first2yoffollow-up generally strengthened
our results. Additional adjustment for intake of vegetables, dairy
products, and meat changed the risk estimates only slightly.
The association between the intake of menaquinones from
meat or meat products or of those from dairy products and the risk
of prostate cancer is shown in Table 4. Only menaquinones from
dairy products were associated with a significantly lower risk of
advanced prostate cancer. Accordingly, the risk estimate for
higher menaquinones (MK-5–9), predominantly (85% of total
intake) derived from dairy products, was close to significance
(RR: 0.82; 95% CI: 0.67, 1.02), whereas the risk estimate for
MK-4 (37% of total intake derived from meat or meat products)
was not significant (Table 5).
In our study population, 48% of all men had undergone 1
PSA test during follow-up; these tests had resulted in the detec-
tion of many occurrences of the early forms of prostate cancer,
whereas similar malignant transformations remain undetected in
men (noncases) who did not undergo PSA testing. When we
restricted our cohort to men who had 1 PSA test, risk estimates
were similar to those obtained in the total cohort (data not
shown).
DISCUSSION
To the best of our knowledge, this report provides the first
analysis of observational data on the association between dietary
intake of vitamin K and the risk of prostate cancer. With higher
intakes of menaquinones, prostate cancer risk decreased; this
association was significant for advanced prostate cancer, espe-
cially with MK-5–9 provided by dairy products. In contrast,
phylloquinone intake was not related to prostate cancer.
According to experimental data, the anticancer activity of the
natural K vitamins phylloquinone and menaquinones is mediated
by antiproliferative effects through induction of proto-
oncogenes such as c-myc and c-fos, which foster cell cycle arrest
and induce apoptosis in several cancer cell lines (3, 5). Most of
these studies found distinct growth-inhibitory effects of mena-
quinones (5–9, 11), whereas substantially weaker (5, 11) or no (6,
9) effects were observed for phylloquinone. These findings seem
to be reflected by our results, which showed a significant inverse
association of total menaquinone intake with advanced prostate
cancer and no associations for phylloquinone. Besides possible
differential anticarcinogenic effects on the cellular level, the
differing results obtained for phylloquinone and menaquinones
may be related to differences regarding bioavailability, half-life,
and tissue distribution (21). Phylloquinone, which is mainly pro-
vided by vegetables and other plant products, is tightly bound to
the chloroplast membranes and therefore is less efficiently ab-
sorbed (5–15% bioavailable) than are menaquinones, which oc-
cur dissolved in the fat-fraction of dairy products or in meat (19,
22). Menaquinones have a substantially longer half-life in the
blood circulation than does phylloquinone (19), and, therefore,
they are available longer to develop anticancer activities. Finally,
menaquinones are more likely to accumulate in extrahepatic
tissues, because they, unlike phylloquinone, are redistributed by
the liver via low- and high-density lipoproteins to extrahepatic
organs (2, 23, 24). Although no data exist to date showing the
concentrations of menaquinones in human or animal prostate, it
is conceivable that menaquinones also accumulate in the prostate
as they do in the pancreas, kidney, and brain (2, 24). However,
TABLE 4
Relative risk of prostate cancer according to dietary intake of
menaquinones from major food sources in men of the EPIC-Heidelberg
cohort
1
Menaquinones
from meat and
meat products
Menaquinones
from dairy
products
Total prostate cancer (n ҃ 268)
Age-stratified 0.81 (0.62, 1.07) 0.96 (0.88, 1.06)
Multivariate
2
0.83 (0.59, 1.17) 0.94 (0.84, 1.06)
Advanced prostate cancer (n ҃ 113)
Age-stratified 0.86 (0.56, 1.32) 0.82 (0.69, 0.97)
Multivariate
2
0.84 (0.50, 1.41) 0.79 (0.63, 0.98)
1
All values are continuous relative risk per 10-
g/d increment; 95% CI
in parentheses. EPIC, European Prospective Investigation into Cancer and
Nutrition. n ҃ 11 319.
2
Cox proportional hazards models, adjusted for smoking (never, quit
10 y ago, quit 10 y ago, current 15 cigarettes/d, current 15 ciga-
rettes/d, or other smoking), education (none or primary school, technical
school, secondary school, or university degree), vigorous physical activity
(none, 2h/wk, or 2h/wk), phylloquinone, menaquinones from other
sources, energy from fat, alcohol, nonfat-nonalcohol energy, calcium, vita-
min D, tomato or tomato products (all nutrients entered as quartile-dummies),
BMI, history of diabetes, and family history of prostate cancer.
TABLE 5
Relative risk of prostate cancer according to intake of menaquinone-4
(MK-4) and MK-5–9 in men of the EPIC-Heidelberg cohort
1
MK-4
2
MK-5–9
3
Total prostate cancer (n ҃ 268)
Age-stratified 0.89 (0.71, 1.12) 0.98 (0.88, 1.08)
Multivariate
4
0.80 (0.55, 1.17) 0.96 (0.85, 1.09)
Advanced prostate cancer (n ҃ 113)
Age-stratified 0.94 (0.66, 1.34) 0.82 (0.68, 0.99)
Multivariate
4
0.71 (0.40, 1.27) 0.80 (0.64, 1.00)
1
All values are continuous relative risk per 10-
g increment; 95% CIs
in parentheses. EPIC, European Prospective Investigation into Cancer and
Nutrition. n ҃ 11 319.
2
Meat and meat products as the main contributors (37% of total intake).
3
Dairy products as the main contributors (85% of total intake).
4
Cox proportional hazard models, adjusted for smoking (never, quit
10 y ago, quit 10 y ago, current 15 cigarettes/d, current 15 ciga-
rettes/d, or other smoking), education, vigorous physical activity (none,
2h/wk, or 2h/wk), phylloquinone, MK-10 –14, energy from fat, alcohol,
nonfat-nonalcohol energy, calcium, vitamin D, tomato or tomato products
(all nutrients entered as quartile-dummies), BMI, history of diabetes, and
family history of prostate cancer.
990 NIMPTSCH ET AL
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because of the tissue-specific conversion of phylloquinone to
MK-4 (2, 23–25), the extent to which the menaquinone content
of extrahepatic tissues is attributable to dietary intake of mena-
quinones or phylloquinone is unclear.
The inverse association between the intake of menaquinones
and the risk of prostate cancer persisted after additional adjust-
ment for main food sources of vitamin K, including dairy prod-
ucts and meat, which suggests that the observed effects are un-
likely to be attributable to the coexistence of other nutrients with
menaquinones in the same foods. We found menaquinones from
dairy products to be more strongly associated with advanced
prostate cancer incidence than were menaquinones from meat or
meat products. Meat and meat products mainly contain MK-4
(and small amounts of menaquinones above MK-9), whereas the
menaquinones MK-5–9 are almost exclusively found in fer-
mented dairy products. This led us to the separate evaluation of
MK-4 and MK-5–9 in relation to prostate cancer. The reduced
RR of advanced prostate cancer was close to statistical signifi-
cance for menaquinones MK-5–9 (provided to 82% by dairy
products), which was not the case for MK-4 (main food source:
meat or meat products, providing 37% of total intake). The dif-
ferences in anticancer effects may be seen as a consequence of the
longer half-life of MK-5–9 in the blood circulation than of MK-4
(25). Because menaquinones MK-10 –14 contribute 4% of to-
tal menaquinone intake and differ with respect to the food source
from MK-5 to MK-9, they were not separately analyzed.
Our findings of stronger associations of vitamin K intake with
advanced than with total prostate cancer could be a hint that
menaquinones play a role in tumor promotion and progression
rather than in tumor initiation. The anticancer actions of the
natural K vitamins are mediated by oncogene-associated cell
cycle arrest and apoptosis, which are likely to play a major role
in the promotion phase, a reversible process lasting several years
and therefore most susceptible to the influence of cancer-
preventive agents (26).
A limitation of the present study lies in the inaccuracies of
dietary vitamin K intake estimation. The vitamin K content of a
certain food may vary considerably, according to the type of
plant, the various agricultural and manufacturer practices, sea-
sonal variation, and maturity (27). In a food-composition data-
base, this variation is usually subsumed in a single value for a
certain food. Moreover, an FFQ is a dietary assessment instru-
ment with limited ability to determine absolute intakes. How-
ever, these uncertainties would attenuate the observed associa-
tion between dietary vitamin K intake and prostate cancer; ie, the
true association would be even stronger. The database for the
phylloquinone content in food that we used (18) includes 2000
foods commonly consumed in Western Europe. It is based on
data from laboratory analyses conducted by Bolton-Smith et al,
other sources of direct HPLC analyses, and recipe calculation
and assignment of values by food similarities. This database was
used successfully for the estimation of phylloquinone intake in
epidemiologic studies (28, 29), in which intake data were also
compared with plasma vitamin K concentrations. Therefore, we
applied the database of Bolton-Smith et al (18) to our data with-
out further modification according to data on the phylloquinone
content of foods published by other researchers (30 –33).
Habitual dietary intake of menaquinones has rarely been cal-
culated (34, 35). The menaquinone food table of Schurgers et al
(19) comprises contents of MK-4 to MK-10 for 30 food items,
although MK-10 was not detected in any of the samples. Mena-
quinones above MK-10 occur in detectable amounts only in
some offal, and thus they play a minor role in human nutrition
(20, 36). Nevertheless, we supplemented the menaquinone data
of Schurgers et al with data on the content of MK-10 –14 in some
pork, beef, and chicken offal (20) that was eventually consumed
in EPIC-Heidelberg. Other data on the menaquinone content of
foods have been published (30 –32). However, only the 2 chosen
data sources analyzed the complete spectrum of MK-4 up to
MK-10 or MK-14, respectively, and therefore allowed a valid
calculation of total menaquinone intake.
The mean phylloquinone intake calculated from the EPIC-
Heidelberg FFQ data was higher than the intakes in 2 studies
using the database of Bolton-Smith et al (18), in which dietary
intake was assessed by food records; those mean values in men
were 70 and 84
g/d, respectively (27, 37). In a Dutch study (34)
assessing intake of menaquinones by using an FFQ and the da-
tabase of Schurgers et al (19), intakes in males (mean: 31
g/d)
fit well with our results. Differences in the dietary assessment
methods (38), differing age ranges, and food preferences of the
populations may explain the slightly diverging results.
According to our data, dairy products contribute 60% to total
intake of menaquinones, and it seems that menaquinones from
dairy products have a more pronounced effect than those from
meat products. These observations contrast with those from nu-
merous prospective studies that suggest a positive association
between the intake of dairy products, especially dairy calcium,
and prostate cancer (39). However, in the present study, all mul-
tivariate analyses were adjusted for dietary calcium intake, and
additional adjustment for dairy products did not affect the results
significantly. Among the group of dairy products, cheese is the
predominant source of menaquinones, whereas calcium is pro-
vided about equally by cheese and milk or milk products (40). A
diet characterized by a moderate calcium intake, therefore, does
not necessarily conflict with a diet high in menaquinones pro-
vided by cheese. The strengths of the present study include the
prospective design, the ability to identify advanced prostate can-
cer cases, the information on PSA screening tests during follow-
up, and the consideration of menaquinones, which are neglected
in most studies on vitamin K because of their lower contribution
to total vitamin K intake.
In summary, we found inverse associations between the di-
etary intake of menaquinones and the risk of prostate cancer. The
associations were strongest for menaquinones from dairy prod-
ucts and in advanced cancer cases. Because the present study is
presumably the first observational study on this topic, the results
warrant confirmation by other studies.
We thank all participants of the EPIC-Heidelberg cohort study for their
continuous collaboration.
The authors’ responsibilities were as follows: KN: statistical analysis,
interpretation of the data, and drafting of the manuscript; SR: critical revision
of the manuscript; and JL: the study concept and design, acquisition of data,
critical revision of the manuscript, and obtaining the funding for the study.
None of the authors had any personal or financial conflict of interest.
REFERENCES
1. Shearer MJ. Vitamin K: metabolism and nutriture. Blood Rev 1992;6:
92–104.
2. Thijssen HH, Drittij-Reijnders MJ, Fischer MA. Phylloquinone and
menaquinone-4 distribution in rats: synthesis rather than uptake deter-
mines menaquinone-4 organ concentrations. J Nutr 1996;126:537– 43.
VITAMIN K INTAKE AND RISK OF PROSTATE CANCER 991
by guest on May 11, 2011www.ajcn.orgDownloaded from
Page 7
3. Lamson DW, Plaza SM. The anticancer effects of vitamin K. Altern Med
Rev 2003;8:303–18.
4. Verrax J, Cadrobbi J, Delvaux M, et al. The association of vitamins C and
K3 kills cancer cells mainly by autoschizis, a novel form of cell death.
Basis for their potential use as coadjuvants in anticancer therapy.
EurJ Med Chem 2003;38:451–7.
5. Nishikawa Y, Carr BI, Wang M, et al. Growth inhibition of hepatoma
cells induced by vitamin K and its analogs. J Biol Chem 1995;270:
28304 –10.
6. Bouzahzah B, Nishikawa Y, Simon D, Carr BI. Growth control and gene
expression in a new hepatocellular carcinoma cell line, Hep40: inhibi-
tory actions of vitamin K. J Cell Physiol 1995;165:459 67.
7. Tokita H, Tsuchida A, Miyazawa K, et al. Vitamin K2-induced antitu-
mor effects via cell-cycle arrest and apoptosis in gastric cancer cell lines.
Int J Mol Med 2006;17:235– 43.
8. Otsuka M, Kato N, Shao RX, et al. Vitamin K-2 inhibits the growth and
invasiveness of hepatocellular carcinoma cells via protein kinase A
activation. Hepatology 2004;40:243–51.
9. Wang Z, Wang M, Finn F, Carr BI. The growth inhibitory effects of
vitamins K and their actions on gene expression. Hepatology 1995;22:
876 82.
10. Okayasu H, Ishihara M, Satoh K, Sakagami H. Cytotoxic activity of
vitamins K1, K2 and K3 against human oral tumor cell lines. Anticancer
Res 2001;21:2387–92.
11. Wu FY, Liao WC, Chang HM. Comparison of antitumor activity of
vitamins K1, K2 and K3 on human tumor cells by two (MTT and SRB)
cell viability assays. Life Sci 1993;52:1797– 804.
12. Habu D, Shiomi S, Tamori A, et al. Role of vitamin K2 in the develop-
ment of hepatocellular carcinoma in women with viral cirrhosis of the
liver. JAMA 2004;292:358 61.
13. Venugopal M, Jamison JM, Gilloteaux J, et al. Synergistic antitumour
activity of vitamins C and K3 against human prostate carcinoma cell
lines. Cell Biol Int 1996;20:787–97.
14. Jamison JM, Gilloteaux J, Taper HS, Summers JL. Evaluation of the in
vitro and in vivo antitumor activities of vitamin C and K-3 combinations
against human prostate cancer. J Nutr 2001;131(suppl):158S– 60S.
15. Boeing H, Korfmann A, Bergmann MM. Recruitment procedures of
EPIC-Germany. European Investigation into Cancer and Nutrition. Ann
Nutr Metab 1999;43:205–15.
16. Bohlscheid-Thomas S, Hoting I, Boeing H, Wahrendorf J. Reproduc-
ibility and relative validity of energy and macronutrient intake of a food
frequency questionnaire developed for the German part of the EPIC
project. European Prospective Investigation into Cancer and Nutrition.
Int J Epidemiol 1997;26(suppl):S71– 81.
17. Al Delaimy WK, Ferrari P, Slimani N, et al. Plasma carotenoids as
biomarkers of intake of fruits and vegetables: individual-level correla-
tions in the European Prospective Investigation into Cancer and Nutri-
tion (EPIC). Eur J Clin Nutr 2005;59:1387–96.
18. Bolton-Smith C, Price RJ, Fenton ST, Harrington DJ, Shearer MJ. Com-
pilation of a provisional UK database for the phylloquinone (vitamin K1)
content of foods. Br J Nutr 2000;83:389 –99.
19. Schurgers LJ, Vermeer C. Determination of phylloquinone and mena-
quinones in food. Effect of food matrix on circulating vitamin K con-
centrations. Haemostasis 2000;30:298 –307.
20. Hirauchi K, Sakano T, Notsumoto S, et al. Measurement of K vitamins
in animal tissues by high-performance liquid chromatography with fluo-
rimetric detection. J Chromatogr 1989;497:131–7.
21. Vermeer C, Schurgers LJ. A comprehensive review of vitamin K and
vitamin K antagonists. Hematol Oncol Clin North Am 2000;14:339 –53.
22. Gijsbers BL, Jie KS, Vermeer C. Effect of food composition on vitamin
K absorption in human volunteers. Br J Nutr 1996;76:223–9.
23. Ronden JE, Thijssen HH, Vermeer C. Tissue distribution of K-vitamers
under different nutritional regimens in the rat. Biochim Biophys Acta
1998;1379:16 –22.
24. Thijssen HH, Drittij-Reijnders MJ. Vitamin K status in human tissues:
tissue-specific accumulation of phylloquinone and menaquinone-4. Br J
Nutr 1996;75:121–7.
25. Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of
K-vitamins in healthy subjects. Biochim Biophys Acta 2002;1570:27–
32.
26. Sun SY, Hail N Jr, Lotan R. Apoptosis as a novel target for cancer
chemoprevention. J Natl Cancer Inst 2004;96:662–72.
27. Thane CW, Paul AA, Bates CJ, Bolton-Smith C, Prentice A, Shearer
MJ. Intake and sources of phylloquinone (vitamin K1): variation with
socio-demographic and lifestyle factors in a national sample of British
elderly people. Br J Nutr 2002;87:605–13.
28. Thane CW, Bates CJ, Shearer MJ, et al. Plasma phylloquinone (vitamin
K1) concentration and its relationship to intake in a national sample of
British elderly people. Br J Nutr 2002;87:615–22.
29. Collins A, Cashman KD, Kiely M. Phylloquinone (vitamin K1) intakes
and serum undercarboxylated osteocalcin levels in Irish postmenopausal
women. Br J Nutr 2006;95:982– 8.
30. Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL. Vitamin K
contents of meat, dairy, and fast food in the U.S. Diet J Agric Food Chem
2006;54:463–7.
31. Ferreira DW, Haytowitz DB, Tassinari MA, Peterson JW, Booth SL.
Vitamin K contents of grains, cereals, fast-food breakfasts, and baked
goods. J Food Sci 2006;71(suppl):S66 –70.
32. Koivu-Tikkanen TJ, Ollilainen V, Piironen VI. Determination of phyl-
loquinone and menaquinones in animal products with fluorescence de-
tection after postcolumn reduction with metallic zinc. J Agric Food
Chem 2000;48:6325–31.
33. Koivu-Tikkanen TJ, Piironen VI, Henttonen SK, Mattila PH. Determi-
nation of phylloquinone in vegetables, fruits, and berries by high-
performance liquid chromatography with electrochemical detection. J
Agric Food Chem 1997;45:4644 –9.
34. Geleijnse JM, Vermeer C, Grobbee DE, et al. Dietary intake of mena-
quinone is associated with a reduced risk of coronary heart disease: the
Rotterdam Study. J Nutr 2004;134:3100 –5.
35. Schurgers LJ, Geleijnse JM, Grobbee DE, et al. Nutritional intake of
vitamins K1 (phylloquinone) and K2 (menaquinone) in the Netherlands.
J Nutr Environ Med 1999;9:115–22.
36. Shearer MJ, Bach A, Kohlmeier M. Chemistry, nutritional sources,
tissue distribution and metabolism of vitamin K with special reference to
bone health. J Nutr 1996;126(suppl):S1181– 6.
37. Duggan P, Cashman KD, Flynn A, Bolton-Smith C, Kiely M. Phyllo-
quinone (vitamin K1) intakes and food sources in 18 64-year-old Irish
adults. Br J Nutr 2004;92:151– 8.
38. Thompson FE, Subar AF. Dietary assessment methodology. In:
Coulston AM, Rock CL, Mousen ER, eds. Nutrition in the prevention
and treatment of disease. London, United Kingdom: Academic Press
2007:3–30.
39. Gao X, LaValley MP, Tucker KL. Prospective studies of dairy product
and calcium intakes and prostate cancer risk: a meta-analysis. J Natl
Cancer Inst 2005;97:1768 –77.
40. Döring A, Honig-Blum K, Winkler G, Kammerlohr R, Fischer B, Keil U.
MONICA Project Region Augsburg. Data book. Dietary surveys
1984/85 and 1994/95 in middle-aged men from the city of Augsburg.
Neuherberg, Germany: GSF-Forschungszentrum, 1998.
992 NIMPTSCH ET AL
by guest on May 11, 2011www.ajcn.orgDownloaded from
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  • Source
    • "In view of VK2 potential to reduce osteoporosis [13] and atherosclerosis risk [4] and given the fact that these two pathologies are frequently associated with prostate cancer patients undergoing hormonal therapy [14] [15], development of VK2 as a treatment strategy for prostate cancer would have far reaching impact on prostate cancer patients. Previously, Nimptsch et al. showed an inverse relationship between dietary intake of VK2 and risk of prostate cancer [16]. Interestingly, serum undercarboxylated osteocalcin (ucOC), a biomarker of vitamin k status, is inversely associated with VK2 intake and the development of advanced prostate cancer [17]. "
    [Show abstract] [Hide abstract] ABSTRACT: In recent years, several studies have shown that vitamin k2 (VK2) has anticancer activity in a variety of cancer cells. The antitumor effects of VK2 in prostate cancer are currently not known. In the present study, we sought to characterize the anticancer potential of VK2 in both androgen-dependent and -independent prostate cancer cells. Our investigations show that VK2 is able to suppress viability of androgen-dependent and androgen-independent prostate cancer cells via caspase-3 and -8 dependent apoptosis. We also show that VK2 treatment reduces androgen receptor expression and PSA secretion in androgen-dependent prostate cancer cells. Our results also implicate VK2 as a potential anti-inflammatory agent, as several inflammatory genes are downregulated in prostate cancer cells following treatment with VK2. Additionally, AKT and NF-kB levels in prostate cancer cells are reduced significantly when treated with VK2. These findings correlated with the results of the Boyden chamber and angiogenesis assay, as VK2 treatment reduced cell migration and angiogenesis potential of prostate cancer cells. Finally, in a nude mice model, VK2 administration resulted in significant inhibition of both androgen-dependent and androgen-independent tumor growth. Overall, our results suggest that VK2 may be a potential therapeutic agent in the treatment of prostate cancer.
    Full-text · Article · Aug 2013 · Evidence-based Complementary and Alternative Medicine
  • Source
    • "Preclinical studies show that the combination of vitamins C and K has potent antitumor activity in vitro and acts as a chemo-and radiosensitizer in vivo [68]. To date, few studies have investigated this, although one study using the European Prospective Investigation into Cancer and Nutrition-Heidelberg cohort found an inverse relationship between vitamin K intake and PCa incidence [78]. Calcium is an alkaline earth metal critical for normal physiology. "
    [Show abstract] [Hide abstract] ABSTRACT: CONTEXT: Prostate cancer (PCa) remains one of the most diagnosed malignancies in the world, correlating with regions where men consume more of a so-called Western-style diet. As such, there is much interest in understanding the role of lifestyle and diet on the incidence and progression of PCa. OBJECTIVE: To provide a summary of published literature with regard to dietary macro- and micronutrients and PCa incidence and progression. EVIDENCE ACQUISITION: A literature search was completed using the PubMed database for all studies published on diet and PCa in June 2012 or earlier. Primary literature and meta-analyses were given preference over other review articles when possible. EVIDENCE SYNTHESIS: The literature was reviewed on seven dietary components: carbohydrates, protein, fat and cholesterol, vegetables, vitamins and minerals, and phytochemicals. Current literature linking these nutrients to PCa is limited at best, but trends in the published data suggest consumption of carbohydrates, saturated and ω-6 fats, and certain vitamin supplements may promote PCa risk and progression. Conversely, consumption of many plant phytochemicals and ω-3 fatty acids seem to slow the risk and progression of the disease. All other nutrients seem to have no effect or data are inconclusive. A brief summary about the clinical implications of dietary interventions with respect to PCa prevention, treatment, and survivorship is provided. CONCLUSIONS: Due to the number and heterogeneity of published studies investigating diet and PCa, it is difficult to determine what nutrients make up the perfect diet for the primary and secondary prevention of PCa. Because diets are made of multiple macro- and micronutrients, further prospective studies are warranted, particularly those investigating the relationship between whole foods instead of a single nutritional component.
    Full-text · Article · Nov 2012 · European Urology
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    Preview · Article · Oct 2008 · Sciences des Aliments
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