Page 1
2008
Paper 4150 139
A B S T R A C T
REVIEW
Molecular basis of the potential
of vitamin D to prevent cancer
Betty A. Ingraham, Beth Bragdon and Anja Nohe
University of Maine, Orono, ME, USA
Address for correspondence: Betty Ingraham, University of Maine, 5737 Jenness Hall, Orono,
ME 04469‑5737, USA. Tel.: +1 207 581 3480; Fax: +1 207 581 2323; bingraham@umche.maine.edu
Key words: Apoptosis – Calcitriol – Cancer – Cell cycle checkpoint – Chemoprevention –
Nuclear receptor – Vitamin D – Vitamin D receptor (VDR)
Introduction
Cancer is a common disease affecting millions world
wide. In the United States, it is the leading cause of
death for individuals under the age of 85
that the cellular environment is the most crucial
determinant of whether a cell becomes cancerous.
1. It is believed
A recent study by Lichtenstein et al.
of twins with cancer indicated that inherited genetic
factors make only a minor contribution to the
development of cancer, commonly estimated to be
approximately 5% of all cases. Their study suggested
that as many as onethird to twothirds of cancers
could be prevented by dietary factors.
2 of 44
788 pairs
Objective: To review current research findings
in cell biology, epidemiology, preclinical, and
clinical trials on the protective effects of vitamin D
against the development of cancers of the
breast, colon, prostate, lung, and ovary. Current
recommendations for optimal vitamin D status,
the movement towards revision of standards, and
reflections on healthy exposure to sunlight are
also reviewed.
Search methodology: A literature search was
conducted in April and updated in September
2007. The Medline and Web of Knowledge
databases were searched for primary and review
articles published between 1970 and 2007, using
the search terms ‘vitamin D’, ‘calcitriol’, ‘cancer’,
‘chemoprevention’, ‘nuclear receptor’, ‘vitamin D
receptor’, ‘apoptosis’, ‘cell cycle’, ‘epidemiology’,
and ‘cell adhesion molecule’. Articles that focused
on epidemi ological, preclinical, and clinical
evidence for vitamin D’s effects were selected and
additional articles were obtained from reference
lists of the retrieved articles.
Findings: An increasing body of research supports
the hypothesis that the active form of vitamin D
has significant, protective effects against the
development of cancer. Epidemiological studies
show an inverse association between sun exposure,
serum levels of 25(OH)D, and intakes of vitamin D
and risk of developing and/or surviving cancer. The
protective effects of vitamin D result from its role
as a nuclear transcription factor that regulates cell
growth, differentiation, apoptosis and a wide range
of cellular mechanisms central to the development
of cancer. A significant number of individuals have
serum vitamin D levels lower than what appears to
protect against cancer, and the research community
is currently revising the guidelines for optimal
health. This will lead to improved public health
policies and to reduced risk of cancer.
Conclusions: Research strongly supports the
view that efforts to improve vitamin D status
would have significant protective effects against
the development of cancer. The clinical research
community is currently revising recom mendations
for optimal serum levels and for sensible levels
of sun exposure, to levels greater than previously
thought. Currently, most experts in the field believe
that intakes of between 1000 and 4000
lead to a more healthy level of serum 25(OH)D, at
approximately 75
protection effects against cancers of the breast,
colon, prostate, ovary, lungs, and pancreas. The first
randomized trial has shown significant protection
against breast cancer, and other clinical trials will
follow and ultimately lead to improved public health
policies and significantly fewer cancers.
IU will
nmol/L that will offer significant
CurreNt MedICAl reseArCh ANd OpINION®
Vol. 24, No. 1, 2008, 139–149
© 2008 lIBrAphArM lIMIted
0300-7995
doi:10.1185/030079907X253519
All rights reserved: reproduction in whole or part not permitted
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140 Molecular basis of vitamin D to prevent cancer
© 2008 lIBrAphArM ltd – Curr Med res 2008; 24(1)
Over more than 20 years, epidemiological and
pre clinical studies have provided evidence that
vitamin D has significant protective effects against
the development of cancer. To review these findings,
a literature search was conducted in April 2007 and
updated in September 2007. The Medline and Web
of Knowledge databases were searched for primary
and review articles published between 1970 and 2007,
using the search terms ‘vitamin D’, ‘calcitriol’, ‘cancer’,
‘chemoprevention’, ‘nuclear receptor’, vitamin D
receptor’, ‘apoptosis’, ‘cell cycle’, ‘epidemiology’,
and ‘cell adhesion molecule’. Articles that focused on
epidemiological, preclinical, and clinical evidence for
vitamin D’s effects were selected and additional articles
were obtained from reference lists of the retrieved
articles. An overview is presented of vitamin D, cancer,
and calcitriol’s effect on cellular transformation.
Epidemiological studies
The initial indications of vitamin D’s protective effects
came from epidemiological studies first published
decades ago and pioneered by Garland, Grant,
Schwartz, Giovannucci, and others
included ecologic examinations of the relationship of
sun exposure, season of diagnosis (indirect measures of
vitamin D status), dietary intake, and serum 25(OH)D
to both the incidence and mortality of cancer.
In an early study, Garland et al.
tions between sunlight and the mortality and incidence
of breast cancer in the United States. Sunlight measure
ments were obtained from the US National Oceanic and
Atmospheric Administration in 87 US locations over a
year. Mortality rates were obtained from the National
Cancer Institute. Their study found a strong, inverse
association (–0.80, p < 0.0001) between sunlight and
breast cancer mortality. The same protective effect has
been found for melanoma
organs
Season of diagnosis, another surrogate measure
of vitamin D status, has also been shown to affect
survival. Porojnicu et al. showed increased survival of
breast cancer in Norway when diagnosis occurred in
summer or autumn, when serum 25(OH)D levels are
higher
prostate cancer
Improved mortality rates for diagnosis when serum
25(OH)D levels tend to be highest have been found
in wideranging geographical areas including the US
Japan
The protective effects of exposure to sunlight (re duced
cancer incidence and mortality) are recognized as being
due to increased serum levels of 25(OH)D – the best
indicator of vitamin D status. In population studies of
3–16. These studies
17 looked for associa
18, cancers of the digestive
4,20, and prostate
19, colon
21,22.
23. The same survival effect has been found for
8,22, and in melanoma
24 among others.
3,
25, Norway
23, Spain
26, and the USSR
27.
serum 25(OH)D, the higher the level of serum 25(OH)
D, the lower the risk of developing cancers of the breast,
colon, prostate, ovary, lung, and systemic cancers in
general. For example, Garland et al.
analysis of serum 25(OH)D levels and the incidence of
breast cancer. They reported a dose–response association
for serum levels in the lowest to the highest quintiles of
serum 25(OH)D; for levels at 6, 18, 29, 37, and 48
they found pooled odds ratios of incident breast cancer
of 1.00, 0.90, 0.70, 0.70, and 0.50. This suggests that
individuals with serum 25(OH)D levels above 48
have half the risk of developing breast cancer. Other
studies comparing serum 25(OH)D levels and cancer
incidence show similar relative risks ranging between 20
and 80%. Some of these studies are noted in Table 1.
Lastly, dietary studies of vitamin D intake also
con sistently find a significant protective effect. For
example, Lin et al. recently published the results
of their prospective study, looking at breast cancer
occurrence in 31
Study
premenopausal women who consumed the highest
versus the lowest amounts of vitamin D. In another
recently published prospective study which combined
the Health Professionals Followup and Nurses’ Health
Study, the authors found a reduced risk of pancreatic
cancer in individuals consuming the highest versus
lowest amount of vitamin D
Mechanistic studies followed the epidemiological
evidence and demonstrated that the active form of
vitamin D plays a key role in regulating many of
the cellular mechanisms involved in the cancerous
transform ation of cells.
7 conducted a pooled
ng/ml
ng/ml
487 subjects in the Women’s Health
12. They found a reduced risk of about 65% in
28.
Vitamin D sources and
regulatory processes
Vitamin D was identified as a fatsoluble vitamin
by McCollum and Davis in 1922 and found to be
essential for bone formation and the maintenance of
calcium homeostasis
vitamin D, calcitriol (1,25(OH)2D3), is more accurately
described as a steroid hormone that plays a critical
role in a diverse range of biological actions including
the regulation of cell growth and the cell cycle
cellular differentiation
modul ation
cellular signaling pathways
Vitamin D is obtained from the diet, from
fortified foods and supplements (D2 and D3) or
from 7dehydro cholesterol in skin (D3) exposed
to ultraviolet ‘A’ light (Figure 1). Once in the
circulatory system, both forms of the vitamin (i.e.,
D2 and D3) bind to plasma α1globulin (Dbinding
29–33. Since then the active form of
34–42,
43–47, apoptosis
48–52, immune
53,54, and in the integration of hormonal and
55–59.
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Molecular basis of vitamin D to prevent cancer Ingraham et al. 141
Table 1. Epidemiological evidence
Study design
Outcome (incident)
Subjects or
cases
Duration
(years)
Exposure
Findings
(RR, OR, OS)
Reference
Serum 25(OH)D highest vs. lowest quartile
Meta-analysis
Colorectal cancer
Pooled
–
> 37 ng/mL
OR = 0.46
Gorham et al., 2007
Two studies, pooled
Breast cancer
1760
–
Average 48 ng/mL
OR = 0.50
Garland et al., 2007
Case-control, Nurses’ Health Study
Breast cancer
701
< 8
> 41 ng/mL
RR = 0.57
in age > 60
Bertone-Johnson
et al., 2005
Case-control, early stage NSCLC
NSC lung cancer –
survival
447
Average 6
> 21.6 ng/mL
OS = 0.74
Zhou et al., 2007
Ecologic studies
Sun exposure, case control
Breast cancer
972
–
Quartile
Exposure at age
10–19, highest vs.
lowest
OR = 0.65
(95% CI 0.50–0.85)
Knight et al., 2007
North–south gradient, multivariate analysis
Ovarian cancer
incidence
Incidents in
175 countries
2002
Lowest latitude
R2 = 0.49
Garland et al., 2006
Season of diagnosis, survival
Hodgkin’s
lymphoma
3139
Norway
1964–2000
Autumn vs. winter
RR = 0.783
(95% CI –0.62–0.99)
Porojnicu et al.,
2005
Dietary intake
Women’s Health Study, prospective study,
calcium and vitamin D
Breast cancer
31 487
Average =
10
Highest vs. lowest.
HR = 0.65
(premenopausal
women only)
(95% CI 0.40–0.92)
Lin et al., 2007
Prospective study, Health Professionals
Follow-up and Nurses’ Health Study
Pancreatic cancer
122 198
1984–2000
Highest vs. lowest
quintile vitamin D
RR = 0.59
(95% CI 0.40–0.88)
Skinner et al., 2006
Case–control study, Mexico City
Ovarian cancer
84
1995–1997
Highest vs. lowest
tertile
OR = 0.43
(95% CI 0.23–0.80)
Salazar et al., 2002
RR = relative risk; OR = odds ratio; AHR = adjusted hazard ratio; OS = overall survival
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142 Molecular basis of vitamin D to prevent cancer
© 2008 lIBrAphArM ltd – Curr Med res 2008; 24(1)
protein) and are subsequently converted in the
liver by the enzyme 25hydroxylase to 25hydroxy
vitamin D (25(OH)D)
in its inactive form until needed
biologically active vitamin D is needed at the tissue
level, 25(OH)D is enzymatically converted in the
kidney to the active form, 1,25(OH)2D3 (calcitriol)
by 25(OH) vitamin D 1αhydroxylase, a cytochrome
P450 protein, and then circulated to the tissues.
The actions of calcitriol in calcium homeostasis,
control of cell growth and differentiation, cell adhesion,
and apoptosis (controlled cell death) are mediated by
its interaction with the vitamin D receptor (VDR),
a member of the nuclear receptor superfamily
(Figure 2). Vitamin D receptors are present in many
cell types including heart, muscle, breast, colon,
prostate, brain, kidney, bone, intestine, osteoblasts,
and immune cells
cytoplasm, calcitriol binds to its nuclear receptor and
recruits specific molecules to form active complexes
that translocate to the nucleus and subsequently
bind to vitamin D response elements (VDREs) in
the promoters of vitaminD responsive target genes.
Calcitriol’s actions at the promoter regulate cellular
processes in these diverse tissues by either initiating or
suppressing expression whichever is directed by the
complex formed
60. The 25(OH)D remains
29,31,32. When
61
60,62. Upon entry into a cell’s
61.
The actions of calcitriol at the cellular level serve
mainly as links to translate metabolic needs to
cellular action. This involves an intricate network of
coordinated actions of various genes, hormones, and
enzymes in a number of tissues. These actions may
fail when calcitriol is unavailable. An example from a
wellunderstood system involves the development of
rickets. During early childhood, the growth plate of
long bones expands as chondrocytes proliferate and
acquire markers of differen tiation. This is followed
by a precisely timed, pro grammed cell death of
chondrocytes, which are then replaced by bone
If there is insufficient serum 25(OH)D to regulate
these events, apoptosis will not occur and proper
skeletal mineralization will fail, leading to rickets in
children characterized by profound morphological
changes including excess of unmineralized matrix,
abnormal overgrowth of capillaries and fibro blasts, and
disorganized bone formation
Vitamin D insufficiency also has profound effects
on the development of cells of the innate immune
system. In a recent study, Liu et al.
when tuberculosis (M. tuberculosis) infects human
monocytes, activation of the cytochrome p450 enzyme
encoded by the gene Cyp27B1 that converts vitamin D
to its active form is one of the first responses observed.
When calcitriol is available to the cell, it is able to
63.
64.
65 found that
Figure 1. The vitamin D endocrine system
Cholecalciferol
(Skin)
Bound
cholecalciferol
Vitamin D binding protein (DBP)
25-hydroxycholecalciferol [25(OH)D]
(Liver)
1,25-dihydroxycholecalciferol (calciferol)
(kidneys, intestine and autocrine synthesis in many cells)
Increases calcium
retention in kidneys
Increases calcium
absorption in
intestine
Mediates
apoptosis signalsRegulates cell
growth and
differentiation
Induces immune protein
synthesis in response to
challenge (i.e. cathelicidin)
Diet
Fatty fish, fortified
foods, supplements
UV radiation
Sunlight
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Molecular basis of vitamin D to prevent cancer Ingraham et al. 143
synthesize cathelicidin, an antimicrobial peptide that
can destroy the tuberculosis bacteria. When calcitriol
is not available, cathelicidin cannot be synthesized and
the defensive mechanism fails.
Cancer and the role of
vitamin D
The transformation of normal cells to cancer cells
involves a progressive accumulation of genetic and
epigenetic alterations to genes that control cell division,
cell adhesion, and apoptosis. By the time neoplasia has
progressed to malignant disease, multiple alterations
have typically occurred involving at least several
oncogenes, the loss of two or more tumor suppressor
genes, and the loss of the cell’s DNA repair mechanisms
(Figure 3). To metastasize, cancer cells manipulate
adhesion molecules and integrins and break though the
basal lamina to enter the extracellular matrix (ECM).
Once there, the cancer cells secrete metaloproteinases
and collagenases that degrade the ECM – allowing
them access to lymph or blood vessels and to spread to
other organs
Calcitriol regulates a number of genes that are
impli cated in cancerous transformation. For example,
‘Gate keeper’ genes such as p21 and p16 govern the
entry of the cell into the cell cycle. If a cell is damaged,
59.
the ‘gatekeepers’ stop the cell from multiplying until
it can either be repaired or eliminated by apoptosis.
‘Caretaker’ genes, such as BRCA1 and BRCA2,
regulate the cell’s ability to repair damage. When
these genes are deleted or inactivated, more mutations
occur and are propagated. A brief review of calcitriol’s
role in regulating the cell cycle and apoptosis,
inducing expression of cell adhesion molecules, and in
modulation of the βcatenin signaling pathway follows.
Calcitriol, the cell cycle, and regulation of
cell division
Calcitriol’s protective effects against the development
of cancer are due in large part to its role in regulating
the cell cycle
required for normal control of the cell cycle. Normal
cell growth is controlled by regulating the levels and
activity of cyclins and their dependent kinases as well
as the molecular actions of checkpoints at specific
transitions in the cell cycle.
Calcitriol affects cyclin pathways by regulating gene
expression of the proteins p27 and p21 and the con
sequent inhibition of cyclin dependent kinases (CDK)
(Figure 4). The entry and passage through the cell
cycle is regulated by the binding, and changing levels
of p21 and p27. For example, a critical point in the
cell cycle is the passage from G1 to the S interphase,
49,66–70. Calcitriol and a functional VDR are
Figure 2. Calcitriol signaling pathways and role as a nuclear transcription factor
Legend
VDR – Vitamin D receptor, nuclear
VDRE – Vitamin D response element
cAMP – Cyclic AMP
PKA – Protein kinase A
PKC – Protein kinase C
PLC – Phospholipase C
RAS – GTPase, pathway
RXR – Retinoid X receptor
Rapid
response
VDRnuc
Nucleus
VDRE
RXR
Cell cycle arrest
Apoptosis
E-cadherin expression
G-protein
cAMP
PKA
PLC
Ca fluxes
PKC
RAS
Vitamin D
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144 Molecular basis of vitamin D to prevent cancer
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at which time the cells commit to replication of the
genome. As G1 progresses, cyclins of the D class
accumulate, form complexes with, and activate specific
CDKs. These complexes activate the transcription of a
number of genes that are required for entry into the
S phase. Calcitriol and its active complexes interact
with cyclin D and have a protective effect by blocking
cell proliferation
Cell cycle checkpoints serve as surveillance
mechan isms, ensuring that critical transitions occur in
the correct order and with fidelity
in DNA replication, DNA repair, or chromosome
71–73.
74–77. If a problem
replication is detected, a checkpoint is activated
and signals are generated that arrest the cell cycle
(Figure 4). Cell cycle arrest is accomplished by either
promoting inhibitory pathways or by inhibiting
activation pathways. The tumor suppressor gene
Trp53 functions in this way. It is activated in
response to DNA damage and inhibits the cell cycle
by increasing expression of p21 – a CDK inhibitor.
Upregulation of the CDKI p21 may result in cell cycle
arrest and induction of differentiation
antiproliferative effects related to cell cycle control
involving three proteins, p21, p27, and p53
78. Calcitriol has
21,69,79,80 via
Figure 3. Molecular basis of cancer and the modulation of cell fate
Figure 4. Calcitriol and cell cycle checkpoints
DNA DAMAGE /EPIGENTIC ALTERATIONS
NORMAL CELL
Successful DNA repair
Cell cycle arrest
DNA repair
Modulation of cell fate
POTENTIAL CAUSES — FAILURE TO REPAIR
Mutations in regulatory or repair genes
Failure of cell cycle checkpoint mechanisms
Activation of growth-promoting genes
Inactivation of tumor suppressor genes
Inactivation of apoptosis-regulating genes
CANCER
Oxidative stress, carcinogens, viruses
Apoptosis
G1
G2
M
Vit D
S
Vit D role in Checkpoint G1/S
Skp2
Cyclin E-
CDK2
Degradation
Cyclin
D/E/A
CDK
2/4/6
P27 Kip1
P27 Kip1 P
U
P27 Kip1 P
VDR
RXR
Legend
G1– Gap preceding synthesis
M – Mitosis
G2 – Gap preceding mitosis
S – DNA duplication, synthesis
RXR – Retinoid X receptor
VDR – Vitamin D receptor
CDK – Cyclin dependent kinases 2, 4, 6
P27 – Gene
Skp2 – S-phase kinase-associated protein 2
P – Phosphorylated
U – Ubiquinated for degradation
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Molecular basis of vitamin D to prevent cancer Ingraham et al. 145
pathways that are consistent with blocking cells from
progressing to the S phase by suppressing G1/Scdk
and Scdk activities.
Cell cycle control/apoptosis pathway
Nearly all animal tissues maintain homeostasis by
balancing the growth and natural death of cells.
Apo ptosis is a normal part of the development and
the terminal differentiation of cells and organs. For
example, in healthy bone growth, chondrocytes
proliferate until a precise moment, and then undergo
apoptosis in a process mediated by calcitriol. If calcitriol
is unavailable, the growth plate overgrows and becomes
deformed, as seen in rickets.
Apoptosis proceeds in tightly regulated, sequential
steps governed by genes that activate caspases within
the cell. Activated caspases cleave a number of cellular
proteins – activating some and inactivating others.
The resulting substrates may be DNA repair enzymes,
nuclear membrane components, endonucleases,
enzymes involved in RNA splicing, and genes regulating
the cell cycle.
Cancer cells often have disruptions in the pathways
leading to apoptosis, thus damaged cells keep prolif
erating, accumulating mutations, and evading des
truction. For example, mutations to the Trp53 gene
are found in 55–70% of human cancers. Normally p53
responds to DNA damage by stopping the cell cycle. It
acts as a transcription factor and induces a number of
genes encoding caspases that mediate apoptosis. But if
p53 is deficient, the cell avoids destruction and DNA
is not repaired. Calcitriol has been shown to affect cell
cycle checkpoints through p53 and to influence genes
affecting apoptosis, including heat shock proteins
Hsp70 and Hsp90 and Apaf1
41,49,81–87.
Calcitriol, cell adhesion molecules, and
loss of contact inhibition
The loss of contact inhibition is central to the develop
ment of cancer
begin to move, walking along fibers and even across
other cells, behavior normal in early development
but aberrant in mature cells. Calcitriol modulates the
cell adhesion molecule Ecadherin, a transmembrane
protein that helps the cell maintain a polarized
conformation and supports an adherent phenotype
in epithelial cells
(Cdh1) is common in transformed cells and predicts
a poor prognosis
gene since cell adhesion inhibits cell division. In a series
of elegant experiments, Palmer et al. demonstrated
that calcitriol treatment caused cancer cells to change
shape and become more adhesive – similar to a more
88–90. When contact is lost, cells can
44,91,92. Loss of the Ecadherin gene
44. It is considered a tumor suppressor
normal phenotype. Treat ment induced expression of
Ecadherin, which increased significantly as the cells
displayed phenotypic changes. Concurrently, the
cellular location of βcatenin, another celladhesion
molecule, changed dramatically. At the beginning of
treatment, βcatenin was located almost completely
in the nucleus. After treatment it trans located to the
plasma membrane, becoming sequestered. When
βcatenin, which activates c-myc, is sequestered in
the plasma membrane, gene activity is inhibited. This
demonstrated that treatment with calcitriol reduces
cellular mRNA levels of cmyc and other genes
Acquisition of the adhesive phenotype depends on the
treatment agent being present in the culture medium.
When the treatment agent is removed, the cells become
progressively disaggregated.
44.
BRCA-1 and BRCA-2 genes
The BRCA genes, like those encoding Ecadherin,
are tumor suppressor genes that are involved in DNA
repair. Their protein products are localized to the
nucleus where they regulate transcription. Mutations in
these genes can predispose to errors in DNA replication
and cancers of the breast, prostate, and ovaries. Recent
research shows that the gene encoding the breast
cancer susceptibility protein (BRCA1) is a critical
downstream target of calcitriol. Campbell et al.
that treatment of MCF7 cells with calcitriol results in
a 5.7fold increase in BRCA1 protein. VDR expression
is directly correlated with induction of BRCA1.
40 found
Determining healthy levels of
vitamin D to protect against
cancer
The overwhelming evidence from epidemiological,
pre clinical, and clinical trials supports calcitriol’s
preventive effects against development of cancers of the
colon, breast, prostate, ovary, pancreas, and Hodgkin’s
lymphoma. These findings have great potential to
improve public health since nearly all studies of serum
25(OH)D concentration in populations worldwide
show levels significantly below what is considered
healthy
In light of these findings, the research community
is currently reviewing physiological evidence
and data from clinical trials in order to revise the
recommendations on vitamin D intake that would be
optimal for health. The National Academy of Sciences,
Food and Nutrition Board, Institute of Medicine is
responsible for updating nutrient intake guidelines.
When guidelines were last published in 1997, the
suggested dietary intake of vitamin D for adults was
93–101.
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146 Molecular basis of vitamin D to prevent cancer
© 2008 lIBrAphArM ltd – Curr Med res 2008; 24(1)
400
levels of vitamin D must be revised upward
Recently, at the Dietary Refer ence Intakes Research
Synthesis workshop
for individuals with limited sun exposure – intakes
of vitamin D3 in the range of 1000–4000
effectively raise serum levels of 25(OH)D to optimal
levels greater than 75
colleagues
mining new guidelines. The suggested changes are
based on studies that compare disease and dysfunctions
(calcium economy, osteoporotic fractures, falls,
response to infections) to population levels of serum
25(OH)D – and determining optimal levels. They also
report a doseranging experiment used to determine
the level of supplementation (in addition to already
existing inputs from UV exposure and diet) that would
be required to raise serum levels. They found that a
daily oral input of 40
to achieve an increase of 0.7
They reported an example of an individual with serum
25(OH)D of 50
target of 80
their calcula tions, a supplementation of 1714
day would be required. They considered this level of
supplementation to be conservative with no risk of
toxicity.
Currently, the Food and Nutrition Board of the
Institute of Medicine has set 2000
limit for vitamin D supplementation with no adverse
effects. Many researchers in the field believe that this
value should be revised upward
protection against disease. No toxic effects have been
observed even at doses exceeding 10
new guidelines are published, most advise that intakes
of 1000
effect.
IU per day. Most experts now believe that healthy
5,9,102,103.
104, experts suggested that – at least
IU could
nmol/L. Robert Heaney and
93–95 have reviewed the data used in deter
IU of cholecalciferol was required
nmol/L in serum levels
93.
nmol/L. To increase serum levels to a
nmol/L (an increase of 30
nmol/L) using
IU/
IU as the upper
95,105 to gain optimal
000
IU
93. Until
IU are protective and provide no risk of adverse
exposure to sunlight
In the vitamin D endocrine system, sunlight has
historically been the best source of vitamin D.
However, it is well established that UV radiation from
sunlight can increase the risk of skin cancer. Because of
this risk, researchers such as Barbara Gilchrest, of the
Boston University School of Medicine, Department
of Dermat ology, recommend that supplements rather
than sunlight should be used to increase levels of
25(OH)D
community are reassessing whether, and to what
extent, sunlight exposure is considered healthy
is reported that even short exposures to sunlight (5–15
minutes between the hours of 10 a.m. and 3 p.m. on
arms, legs, and the face) can achieve significant gains in
serum levels of vitamin D
106. However, others in the public health
107–115. It
111. This is a level of exposure
less than would cause slight reddening of the skin. Since
strict sun protection can cause vitamin D deficiency
in some groups
to develop new guidelines that take into account the
relative risks and benefits derived from sensible sun
exposure
is needed in this area.
110, some believe that it is important
8,20. As yet there is no consensus and research
Randomized trials of
calcitriol’s effects
Given the strong epidemiological and preclinical
evidence, there is a need for randomized clinical trials
to demonstrate vitamin D’s protective effects. The first
of these has recently reported a significant protective
effect. In this study, Lappe et al.
populationbased, randomized placebocontrolled trial
extending over a 4year period. Fracture risk was the
primary outcome and systemic cancer incidence was
the principal secondary outcome. Subjects received
either calcium alone (1400–1500
vitamin D3 (1100
risks (RR) of incident cancers in the calcium plus D3 to
be 0.402 (
cancers diagnosed after 12 months (eliminating cancers
which might have been present but undiagnosed
at the start of the trial), the RR dropped to 0.232.
These findings support the hypothesis that correcting
vitamin D deficiencies and optimizing serum levels
could significantly reduce the incidence of cancer.
94, conducted a
mg), calcium plus
IU), or placebo. They found relative
p = 0.01). When they confined analysis to
Conclusion
Cancer is the leading cause of death in the United
States and studies suggest that the majority of these
could be prevented by dietary factors affecting the
cellular environment. Epidemiological, preclinical,
and clinical studies provide strong support for the
hypothesis that vitamin D has a significant protective
effect against cellular transformation leading to cancer.
These studies find that the higher the UV exposure,
dietary intake, and serum level of 25(OH)D, the
lower the incidence and mortality from cancers of the
breast, colon, lung, pancreas, prostate, melanoma, and
Hodgkin’s lymphoma. These protective effects are
likely due to calcitriol’s regulatory effects on cellular
mechanisms involved in cancer development including
cell cycle control, apo ptosis, cell adhesion, as well as
regulation of cellular differentiation and proliferation.
The clinical research community is revising guidelines
for vitamin D intake and developing models to define
optimal levels of serum 25(OH)D that protect against
the development of cancer. The new guidelines will
Page 9
© 2008 lIBrAphArM ltd – Curr Med res 2008; 24(1)
Molecular basis of vitamin D to prevent cancer Ingraham et al. 147
likely recommend that serum levels of 25(OH)D
should be above 80
should be in the 1000–4000
where no adverse effects have been observed and that
could lead to more effective public health policies,
resulting in significantly fewer cases of cancer in the
future.
nmol/L and that healthy intakes
IU range. This is a level
Acknowledgments
Declaration of interest: The Maine Cancer Foundation
and the Institute for Molecular Biophysics funded this
research. The authors thank Wesley Beamer of the
Jackson Laboratory for his thoughtful review of the
manuscript.
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Paper CMRO4150_4, Accepted for publication: 23 October 2007
Published Online: 22 November 2007
doi:10.1185/030079908X253519
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