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Vitamins for Cancer Prevention and Treatment: An Insight
A. Jain1, A. Tiwari2, A. Verma2 and S.K. Jain*,2
1Institute of Pharmaceutical Research, GLA University, NH-2, Mathura-Delhi Road, Mathura (U.P.), 281 406 -
India; 2Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh
Gour Central University, Sagar (M.P.), 470 003 - India
Abstract: Over a few decades a strong interlink between oxidative damage and cancer
has been investigated by various scientists across the world on the basis of
epidemiological observations of the effects of fruits and vegetables used in the diet for
cancer patients. Primarily, Vitamin C, Vitamin D and Vitamin E are reported to be
involved in the amelioration of side effects which occur in chemotherapy and radiation
therapy of lungs, stomach, prostate, colorectal, gastric head and neck cancers. The
vitamins acting as antioxidant adjuvants are found to have apoptotic and anti-
angiogenesis potential as well as inhibitory effects against metastasis in cancer cells.
This chapter explicitly discusses the key aspects concerned with the vitamins in relation
to cancer prevention and treatment. It describes vitamins and their natural resources,
role of vitamins in the body, and vitamins as prime ingredients in the diet and their effects
on cancer biology with reference to recent research reports. Moreover, this paper also
includes the emerging potential of pharmaceutical advances to enhance bioavailability of
the vitamins to cancer patients with improved safety and efficacy. Clinicians and
researchers must mull over the nutritional requirements of individual cancer patient so as
to treat cancer and increase life expectancy.
A R T I C L E H I S T O R Y
Received: May 30, 2017
Revised: June 25, 2017
Accepted: July 12, 2017
Keywords: Vitamin, cancer, prevention, treatment, diet, metabolism, targeting.
Vitamins are composed of two words; vital plus
amine means compounds required for normal growth of
body and maintenance of several body functions.
Vitamins are organic molecules that are essential part
of a regular diet. Vitamins or their derivatives act as
coenzymes, cellular antioxidants, and/or regulators of
gene expression. Vitamins are organic compounds
which cannot be produced in human body therefore
they must be provided through the diet . Several
types of vitamins are essentially required for the normal
body functions. They are either of water soluble (folic
acid, cobalamin, ascorbic acid, pyridoxine, thiamine,
niacin, riboflavin, biotin, and pantothenic acid) or fat
soluble (vitamins A, D, K, and E) in nature [2-4].
Different water soluble vitamins are precursors of many
coenzymes which are required for several enzyme
catalyzed metabolism. Fat soluble vitamins do not
show coenzyme function except vitamin K. These
essential vitamins are usually co-absorbed or
transported by different mechanisms. After absorption,
these vitamins normally are not excreted in urine and
stored in liver and adipose tissues in definite amount.
In case of hypervitaminosis, only water soluble vitamins
*Address correspondence to this author at the Pharmaceutics
Research Projects Laboratory, Department of Pharmaceutical
Sciences, Dr. Hari Singh Gour Central University, Sagar (M.P.), 470
003 - India; Tel: +91-9425172184; E-mail: firstname.lastname@example.org
(i.e. B complex and ascorbic acid) are eliminated from
the body while fat soluble vitamins may create serious
toxicological complications [5, 6]. Tables 1 and 2
summarize different water soluble and fat soluble
2. VITAMINS AND THEIR ANALOGS FOR
Since vitamins cannot be made in body in an
adequate amount; they need to be supplemented in
trace amounts through diet. Certain vitamins like biotin
may be synthesized by the intestinal microflora in order
to meet the demands of the host body . They are
the essential components of a diet since the cells are
incapable of synthesizing them in the required
quantities and at adequate rates in order to meet the
demands of the body because of the absence of the
necessary enzymes . Cancer is a serious disease
in which mortality rates of patients have been
increasing per year . About one sixth of all deaths
have been accounted due to cancer in the United
States and many other developed countries . Till
date, various strategies have been developed by the
scientists for its prevention and treatment. Different
pattern antitumoral therapies like surgery,
chemotherapy and radiotherapy have been improved,
but there is an urge for the development of some
innovative approaches for the effective treatment of
cancer. Major proportion of cancer occurring in humans
322 Current Molecular Medicine, 2017, Vol. 17, No. 5 Jain et al.
Table 1. Various fat soluble vitamins.
and fish liver oil
RDA for adults
is 1000 RE for
800 RE for
Regulates the protein
synthesis and thus shows
involvement in the
processes like cell growth
and differentiation. It is
essential for maintaining
healthy epithelial tissue.
Carotenoids (especially β-
carotene) functions as
antioxidants and reduces
the risk of cancers
induced by free radicals
and strong oxidant.
requires vitamin A.
the risk for hip
Vitamin D (pro-
the action of
ultra violet rays
Raises the absorption of
calcium from intestine,
and it also enhances the
mineralization of bone
a in adults.
may lead to
in the liver and
are rich sources
of Vitamin E,
e.g. wheat germ
oil, safflower oil,
cotton seed oil,
and palm oil
5 mg (7.5 IU) /
day and an
mg for each
It functions as a
membrane antioxidant. It
is closely associated with
and prevents sterility.
It increases the synthesis
of heme protein by
enhancing the activity of
aminolevulinic acid (ALA)
synthase and ALA
Bacteria in the
make vitamin K.
chard and turnip
greens as well
30 µg/ day
Synthesis of clotting
factors by acting as co-
enzyme for carboxylation
of glutamic acid
red blood cells
Vitamins for Cancer Prevention and Treatment: An Insight Current Molecular Medicine, 2017, Vol. 17, No. 5 323
Table 2. Various water soluble vitamins.
active form of
vitamin B1 is
Aleurone layer of
wheat flour and
ring and a
ring held by a
1 to 1.5 mg
Transketolase is TPP
dependent in HMP shunt
pathway. Enzyme pyruvate
(oxidative carboxylation) the
irreversible conversion of
pyruvate to acetyl CoA. TPP
has an essential role in the
transmission of nerve.
Co-enzyme functions in the
metabolism of carbohydrates
and branched chain amino
Liver, dried yeast,
egg, and milk
to D- ribitol by
e (FMN) and
1.5 mg per
Redox reactions responsible
for energy production. The
coenzymes, FAD and FMN
are linked with certain
enzymes involved in
carbohydrate, lipid, proteins
and purine metabolism and in
electron transport chain (i.e.
acyl CoA dehydrogenase,
xanthine oxidase, glutathione
reductase, glycine cleavage
dehydrogenase, and alpha
Dried yeast, rice
meat and fish.
About half of the
met by the
niacin. (About 60
mg of tryptophan
will yield 1 mg of
The coenzymes NAD and
NADP are involved in a variety
NADH produced is oxidized in
the electron transport chain for
generation of ATP. [Lactate
dehydrogenase, beta hydroxy
acyl CoA dehydrogenase, and
dehydrogenase are NAD
by a peptide
Coenzyme A acts as a carrier
of activated acetyl or acyl
groups. It is a central molecule
which is involved in all the
lipid and protein)
(Pain and numbness
in the toes,
egg, milk, meat,
fish and green
decarboxylation of amino
acids, ALA synthase, glycogen
(PLP deficiency in
turn leads to niacin
but at higher
(Table 2) Contd….
324 Current Molecular Medicine, 2017, Vol. 17, No. 5 Jain et al.
Vitamin B7 or
egg, yolk, soy
Biotin (Vitamin H
Biotin functions as a carrier of
CO2 in carboxylation reactions
(Acetyl CoA carboxylase,
propionyl CoA carboxylase,
and pyruvate carboxylase
Biotin-avidin reaction is used
in immunosorbent assays.
Anemia, loss of
THF the coenzyme of folic
acid is actively involved in the
one carbon metabolism.
THF functions as an acceptor
or donor of one carbon units
(formyl and methyl, etc.) in a
diversity of reactions involving
synthesis of purine, pyrimidine
and various amino acids.
ring has four
just like a
2 µg/per day
Isomerization of methymalonyl
CoA to succinyl CoA.
Synthesis of methionine from
methyl malonic acid,
breakdown of myelin
interruption in nerve
vitamin C; the
Collagen formation, bone
formation, and metabolism of
tryptophan, tyrosine, heme,
haemoglobin and folic acid
anemia, bone pain,
Vitamin P; rutin
such as green
30 to 200 mg
As antioxidants increases the
effects of various other
antioxidant vitamins. Functions
with vitamin C for
strengthening and protecting
the blood vessel structure, and
lower extended bleeding,
bruising, and nosebleeds. For
treating hemorrhoids and
varicose veins. Functions with
vitamin C to palliate oral
herpes. May aid in preventing
and treating cataracts.
Stimulates the bile production.
Employed in treating sports
injuries. Useful in reducing leg
and back pains. Effect similar
to antibiotic because of anti-
viral, anti-bacterial activity,
anti-allergic and anti-
Inhibits the cancer growth thus
useful in treating tumors.
Decreases the chances of
after injury, like
sports injuries, nose
or varicose veins
and weak immune
system, leading to
frequent colds or
Vitamins for Cancer Prevention and Treatment: An Insight Current Molecular Medicine, 2017, Vol. 17, No. 5 325
is because of various environmental factors [37, 40].
Although tobacco and smoking are the prime causes
which lead to death in cancer patients, it has been
hypothesized that diet plays an essential role in
cancer’s etiology [41, 42]. In recent years, the possible
function of various vitamins in cancer prevention has
been an area of contemplation for the researchers [43-
2.1. Vitamin A
Vitamin A is a fat soluble vitamin which performs
various vital functions of the body (Table 1). The
compounds like retinol and its esters, retinaldehyde
and retinoic acid are the naturally occurring preformed
vitamins. For pharmaceutical applications, some
synthetic compounds called as retinoids have been
produced . Vitamin A was analyzed with respect to
carcinogenesis because of the involvement of cancer
disease in the normal tissue growth and differentiation
disturbance. Experimental studies amongst animals
suggested that susceptibility to certain forms of
chemical carcinogenesis might be increased by
deficiency of vitamin A .
The various mechanisms by which retinoids may
affect carcinogenesis have been authenticated.
Hypotheses of these mechanisms have been
developed to include an action on the cell nucleus
which involves the expression of the genetic
information regulating cell differentiation. The transport
of retinol and retinoic acid within the cell and across the
nuclear membrane is facilitated by certain specific
binding proteins for retinol and retinoic acid which is a
hormone like control of cell differentiation. Besides this,
retinol also has many influences on the cell membrane,
involving altered glycoprotein synthesis and
modifications in membrane receptors for various
hormones, including those mediated by c-AMP. Cell-
cell interactions, cell adhesion, and cell membrane
permeability may be influenced by action on these
receptors . Since, vitamin A (retinol) seems to
possess only restrained anticancer activity at clinically
tolerable doses; its future in cancer treatment
apparently lies with synthetic retinoids (isotretinoin,
etretinate, arotinoids, all transretinoic acids (ATRA),
and 4-HPR [N-(4-hydroxyphenyl) retinamide] or
fenretinide which are more effective and less toxic. APL
(Acute Promyelocytic Leukemia) is disease in which
the therapeutic effects of retinoid chimeric have been
explained by the genes ensuing from the fusion of the
promyelocytic leukemia gene to the gene for retinoic
acid binding receptor on chromosome. Nearly complete
remission in patients with APL was induced by clinical
studies with ATRA as differentiation therapy. Since, the
prolonged use of ATRA (all-trans retinoic acid) or 13-
cis retinoic acid (CRA) produces remarkable side
effects, other synthetic retinoids, like retinamide or
fenretinide, were observed to be quite effective in
breast, prostate, and ovarian carcinoma rendering
minimum toxicity in human beings .
2.2. β-Carotene (Provitamin A)
β-Carotene is one of the few carotenoids that bears
pro-vitamin A activity and is the carotenoid that is most
expeditiously converted to retinol in the human body.
The putative cancer preventive properties of β-
carotene might be depicted by various mechanisms. A
hypothesis has been developed that α-carotene might
be advantageous via local conversion to retinol at
tissue level . After reaching the post-hepatic tissue,
β-carotene has been hypothesized to be capable of
quickly compensating localized retinol deficiencies that
may be stimulated by carcinogens. Its antioxidant
functions could be other essential mode of action.-like
neutralization of free radicals, and intermediates of
metabolism that are quite reactive owing to the
presence of a non-paired electron. These reactive
species by reacting with polyunsaturated fatty acids are
capable of initiating lipid peroxidation, deactivating
proteins and enzymes by reacting with amino acids,
and damaging RNA and DNA by reacting with guanine.
Photochemical reactions and oxidant stress can
generate free radical species for instance induced by
cigarette smoking; free radicals could be an outcome of
normal cell metabolism too. If enzymatic and non-
enzymatic antioxidants safeguard the cell insufficiently,
free radicals can damage cellular structures by reacting
with biomolecules. In animal studies antioxidants have
been involved in both the initiation and promotion
phases. The genetic changes may be prevented by the
antioxidants via prevention of DNA damage directly
induced by free radicals or can show interference with
the metabolic stimulation of chemical carcinogens. Few
synthetic antioxidants like BHT or BHA have been
implied for deriving the hypotheses on the function of
free radicals and antioxidants in tumor promotion. Third
postulated mechanisms of action for β-carotene are
through the immuno-modulatory effects. Since, a signi-
ficant number of human cancers do not demonstrate
any immunogenic properties; the concept of immuno-
regulation of carcinogenesis may only be applied to few
forms of human cancer . Besides the three
mechanisms stated above, few other mechanisms
have been posited for β-carotene which include
alteration of enzymatic activation of (pro)carcinogens
and enhancement of gap junction communication. An
enhancement in the cell to cell communication would
lead to restrict the clonal expansion of initiated cells
and has been described to be imparted on by retinoids
but the effect of carotenoids was independent of their
pro-vitamin A activity .
2.3. Vitamin B
Vitamins B1, B2, B6, B9, B12 and folate are water-
soluble vitamins. Majority of the studies considering
their functions in the treatment are very restricted and
contradictory, with some depicting anticancer activity
and others revealing no activity or cocarcinogenic
action. Nutrition intervention trials conducted in Linxian
(China) employing multiple vitamins (for example,
vitamins B1, B2, B6, and B12 in tablets as diet
326 Current Molecular Medicine, 2017, Vol. 17, No. 5 Jain et al.
supplements for 6 years) did not indicate any
substantial statistical difference in decreased
incidences of esophageal dysplasia in the patients.
Folic acid i.e. leucovorin revealed reduced toxic effects
of 5-FU in the patients suffering from advanced
colorectal carcinoma .
2.4. Vitamin C (Ascorbic Acid)
Vitamin C is a water-soluble antioxidant and
enzyme cofactor found in plants and some animals.
Vitamin C mainly has two chemical forms: the reduced
form (ascorbic acid; AA) and the oxidized form
(dehydroascorbic acid; DHA). Ascorbic acid is the more
prevailing chemical structure in the human body, an
essential micronutrient implied in numerous biological
functions . Vitamin C majorly works as an
antioxidant and free radical scavenger and plays an
essential role in collagen synthesis . Though
concomitant administration of vitamin C inhibits several
types of animal tumor, in other tumors vitamin C
enhances tumor growth and thus, may function as a
cocarcinogen . Positive effects were depicted in
former clinical studies employing high doses of vitamin
C (10 g/daily) in patients suffering with terminal cancer
(viz. breast, colon, bronchus, stomach, rectum, etc.) on
survival and tumor regression; howsoever, a controlled
double-blind trial involving patients suffering from
advanced cancer who obtained vitamin C depicted no
amelioration of symptoms and no regression of tumor
when compared to patients who received just the
2.5. Vitamin D (Calciferol)
Vitamin D, also found from diet and supplements
apart from sunlight, is a fat-soluble compound with
antiproliferative effects involved in bone development
and immune system . Vitamin D in its active form is
lα, 25-dihydroxy vitamin D3, functions via specific
intracellular receptors for modulation of transcription
and control of specific genes (cmyc and c-fos) in a the
same manner as of steroid thyroid hormone family.
This factor is also referred as vitamin D hormone. Its
active form, 1, 25-D (Calcitriol), leads to inhibition of
cancer cell proliferation and replication, and it has been
revealed that vitamin D exerts therapeutic effects on
prostate carcinoma and BPH (benign prostatic
hyperplasia). Because its therapeutic effects are
impeded by hypercalcemic effects, various novel
synthetic derivatives have been synthesized recently.
Synthetic analogs, including R024-553 1 and EB-1089
known as deltanoids, have a decreased hypercalcemic
effect and are potent antitumor agents . Clinical
trials using EB-1089 are currently being investigated for
the treatment of breast cancer .
2.6. Vitamin E
Vitamin E is a lipid soluble vitamin. It works as an
antioxidant in plant and animal tissues. This group
consists of at least eight compounds, called as
tocopherols (α, β, γ, and δ) and tocotrienols; but the
one which is biologically active is α-tocopherol. Vitamin
E has also been demonstrated to be a blocker of
nitrosamine formation. This mechanism would be
essential in the initial stages of carcinogenesis. A
probable mechanism of action for vitamin E in the
promotional stages of carcinogenesis has been
hypothesized as effects on the immune system.
Vitamin E supplementation can rise the generation of
humoral antibodies and enhancement of cell mediated
immunity in both experimental animals and in humans
. Eventually, vitamin E has been hypothesized to
possess antitumor proliferation capacities, possibly by
gene expression modulation especially in the oral, lung,
colorectal, and cervical carcinoma. Nevertheless, no
decrement in the occurrence of lung carcinoma in male
smokers was observed after 5-8 years of dietary
supplementation with α-tocopherol. Disappointing
results were produced by clinical trials employing
vitamin E in cancer treatment and the utilization of
vitamin E in phase I and I1 clinical trials in patients
suffering from metastatic neuroblastonia and
retinoblastoma led only to minor results . Table 3
summarizes different types of vitamins and their
3. EPIDEMIOLOGICAL STUDIES
3.1. Vitamin A
The relation between percentage carotene intake
and status with cancer risk in human has been
investigated by a huge number of observational
epidemiological studies. Though the inverse
association between β-carotene and cancer is strong
for lung carcinoma, an epidemiologic study observed
no decrease in lung carcinoma incidences amidst male
smokers after dietary supplementation with β-carotene
or vitamin E for 5-8 years. A recent study in which a
combination of β-carotene and vitamin A was used to
treat lung carcinoma also revealed no decrease in lung
carcinoma or cardiovascular disease, but showed
deleterious effects, such as 18% rise in lung carcinoma
in smokers and workers exposed to asbestos .
An anticarcinogenic effect was exerted by a new
semisynthetic derivative of canthaxanthin on
experimental mammary adenocarcinoma stimulated by
DMBA and nitrosomethylurea (NMU). Due to its strong
antimitotic presently it is employed in patients suffering
from advanced metastatic breast and lung carcinoma
as a single agent or in combination with navelbine in a
dose of 30 mg/ml monthly, furnishing an overall
response rate of 35% in breast carcinoma ability
(complete response 15% + partial response 20%) or
32% in lung carcinoma (complete response 6% +
partial response 26%) with minimum toxicity, well
tolerability, and a survival time -35 weeks. The risk of
cervical dysplasia, oral leukoplakia, and gastric and
bronchial metaplasia was decreased by β-carotene and
vitamin C . A recent analysis with a 17-year follow-
up too depicted that low plasma levels of vitamins C, A,
and β-carotene elevated the risk and mortality of lung
carcinoma. Hence, the function of β-carotene and its
Vitamins for Cancer Prevention and Treatment: An Insight Current Molecular Medicine, 2017, Vol. 17, No. 5 327
derivatives in the treatment and prevention of cancer is
not conclusive .
3.2. Vitamin C
Among 46 epidemiologic studies in which a dietary
vitamin C index was computed, 33 found statistically
remarkable prevention, with high intakes providing
double the protective effect of low intakes. The
evidence is very strong and consistent for carcinoma of
the esophagus, oral cavity, colon, lung, larynx, and
cervix. And in contrast, the results are inconsistent for
breast, prostate, and ovarian carcinoma. Thus, epide-
miologic studies cannot specify the anticarcinogenic
role of vitamin C alone, because this vitamin is usually
present in combination with other vitamins (E, β-
carotene, and folate) in vitamin C-rich foods .
3.3. Vitamin D
Epidemiological studies have shown both elevated
incidence rates and increased mortality rates in few
cancers in geographical regions or in those populations
which are exposed to less solar ultraviolet B (UV-B)
radiation. Sunlight has been reckoned to be a
surrogate for vitamin D levels, and the potential anti-
cancer benefit in areas exposed to high sunlight is
ascribed to vitamin D production since UV light is
important for the cutaneous synthesis of vitamin D. The
sunlight–vitamin D hypothesis has been intended for
several cancers which include colorectal cancer (CRC),
prostate cancer (PCa) and breast cancer (BCa). Few
studies describe an inverse relation between cancer
risk and circulating levels of 25(OH) D, which depict
both sun exposure and dietary vitamin D intake. The
strongest evidence is for CRC: circulating 25(OH) D
levels and vitamin D intake show an inverse correlation
with colorectal adenoma and CRC incidence. Besides,
in CRC patients, higher prediagnosis plasma 25(OH) D
levels were associated with a remarkable melioration in
overall survival [71, 72].
A recent data analysis from the Women’s Health
Initiative (WHI) randomized trial revealed that estrogen
therapy concurrent with calcium and vitamin D
supplementation raised the chances of developing
CRC. In the women concurrently assigned to placebo
arms (no estrogen) of the estrogen trials, the calcium
and vitamin D supplementation was useful in
decreasing the risk of CRC. The evidence for an
elevated risk of PCa in vitamin D-deficient populations
is quite weaker; an inverse association between serum
25(OH) D levels and PCa risk was suggested by a few
studies whereas, remaining ones do not have such a
correlation. A recent epidemiological analysis of data
led to a conclusion that a 50% reduction in the
incidence of BCa had an association with a serum
25(OH) D level of approximately 52 ng ml−1 (130 nmol
liter−1). Few analysis have examined inconsistently, the
correlation between polymorphisms in the VDR gene
and the risk for colon and prostate cancers, but certain
studies demonstrate a poorer prognosis for certain
single-nucleotide polymorphisms in the VDR gene .
4. SOURCES AND METABOLISM OF VITAMINS
Vitamin D has many sources like diet, fortified foods
and supplements (D2 and D3) or from 7-
dehydrocholesterol in skin (D3) on exposure to
ultraviolet ‘A’ light (Fig. 1). After reaching in the
circulation, both forms of the vitamin (i.e., D2 and D3)
bind to plasma α1-globulin (D-binding protein) followed
by subsequent conversion in the liver through the
enzyme 25-hydroxylase to 25-hydroxyvitamin D
(25(OH) D). The D 25(OH) stays in its inactive form till
required. On requirement biologically active vitamin D
25(OH) D is enzymatically converted to the active form,
1,25(OH)2D3 (calcitriol) in the kidney by 25(OH) vitamin
D 1α-hydroxylase, a cytochrome P450 protein, and
then circulated to various tissues .
5. MECHANISMS OF ANTICANCER ACTIONS
McCollum and Davis identified Vitamin D as a fat
soluble vitamin in the year 1992 and considered it
important for formation of bones and maintenance of
calcium homeostasis . Its active form i.e. calcitriol
(1,25(OH)2D3) plays an essential role in a wide range of
actions which include cell growth regulation, immune
modulation and apoptosis, etc. For converting normal
cells to cancerous cells, a progressive accumulation of
genetic and epigenetic alterations to genes that
regulate the cell division, cell adhesion, and apoptosis
are involved. During the time neoplasia progresses to
malignant disease, multiple alterations usually occur
and involve at least various oncogenes, the loss of two
or more tumor suppressor genes, and the loss of the
cell’s DNA repair mechanisms (Fig. 2). For metastasis,
adhesion molecules are manipulated by the cancer
Table 3. Different types of vitamins and their anticancer activity.
Type of Vitamin
Prostate, lung, basal cell carcinoma (BCC), squamous cell carcinoma, melanoma, dysplastic nevus
syndrome, mycosis fungoides or cutaneous T-cell lymphoma, acute promyelocytic leukemia (APL),
lung carcinoma, breast carcinoma, ovarian carcinoma, bladder carcinoma, and squamous cell
carcinoma of the head and neck.
[37, 52, 60-62]
Breast, melanoma, colon, ovarian, pancreatic cancer, Hodgkin’s lymphoma.
[58, 64, 65]
328 Current Molecular Medicine, 2017, Vol. 17, No. 5 Jain et al.
cells and integrins and the basal lamina is broken in
order to enter the extracellular matrix (ECM). After
reaching there, metalloproteinase and collagenases
are secreted by the cancer cells which in turn degrade
the ECM–permitting them the access to lymph or blood
vessels and to metastasize .
Numerous genes that are implicated in
transformation of cancer are regulated by calcitriol. For
example, ‘Gatekeeper’ genes such as p21 and p16 rule
the entrance of the cell into the cell cycle. The
‘gatekeepers’ cease the cell from multiplying in case if
a cell is damaged till it can either be mended or
eradicated via apoptosis. ‘Caretaker’ genes, such as
BRCA1 and BRCA2 are responsible for the regulation
of the cell’s capacity to repair damage. When these
genes are either deleted or deactivated, further
mutations take place and are propagated .
4.1. Role of Calcitriol (Vitamin D) in Cell Division
Due to its role in controlling the cell cycle, calcitriol
shows protective effects against cancer development
. For general regulation of the cell cycle, Calcitriol
and a functional VDR are needed. Control of normal
cell growth is achieved by modulating the levels and
activity of cyclins and their dependent kinases besides
the molecular actions of checkpoints at particular
transitions in the cell cycle . Calcitriol influences the
cyclin pathways by regulation of gene expression of the
proteins p27 and p21 and the consequent inhibition of
cyclin dependent kinases (CDK) (Fig. 3) . Binding,
and changing levels of p21 and p27 regulate the entry
and transit via the cell cycle. For instance, transit from
G1 to the S interphase is a crucial point at which the
cells confide for the genome replication. With the
progression of G1, complexes of cyclins of the D class
with specific CDKs are formed and in turn activate
CDKs. The transcription of numerous genes which are
necessitated for entry into the S phase is then activated
by these complexes. By interaction with cyclin D,
Calcitriol and its active complexes possess protective
effect by impeding the cell proliferation . Cell cycle
checkpoints by their surveillance mechanisms ensure
that critical transitions happen in the right order and
with fidelity. If any trouble occurs in DNA replication,
DNA repair, or chromosome replication, a checkpoint
gets stimulated and generation of signals occurs in
order to arrest the cycle (Fig. 3).
Cell cycle arrest is achieved by either elevating the
inhibitory pathways or by curbing the activation
pathways. The tumor suppressor gene Trp53 acts in
this manner. DNA damage activates it and in turn it
increases the expression of p21 – a CDK inhibitor,
thereby inhibiting the cell cycle. Upregulation of the
CDKI p21 may lead to the arrest of cell cycle and
induce the differentiation . Antiproliferative effects
are depicted by calcitriol which are related to cell cycle
control involving three proteins, p21, p27, and p53 via
pathways that are consistent with impeding cells from
progressing to the S phase by inhibiting G1/S‑cdk and
4.2. Role of Vitamin D in Apoptosis Induction
Besides the antiproliferative effects of 1α,25(OH)2
D3, few evidences support that 1α,25(OH)2D3 exhibits
anti-tumor effects by controlling the key mediators of
apoptosis, like by repression of the expression of the
anti-apoptotic, pro-survival proteins BCL2 and BCL-XL,
or induction of the expression of proapoptotic proteins
(such as BAX, BAK and BAD) . It has been
demonstrated that BCL2 expression in MCF‑7 breast
tumor and HL‑60 leukaemia cells is down regulated by
1α,25(OH)2D3 and BAX and BAK expression in
prostate cancer, colorectal adenoma and carcinoma
cells is up regulated by 1α,25(OH)2D3 . Apart from
modulating the expression of the BCL2 family,
1α,25(OH)2D3 may also straight away trigger the
caspase effector molecules, although it is ambiguous
Fig. (1). Vitamin D endocrine system.
Vitamins for Cancer Prevention and Treatment: An Insight Current Molecular Medicine, 2017, Vol. 17, No. 5 329
whether apoptosis induced by 1α,25(OH)2D3 is
caspase-dependent. Supporting this idea, the
treatment of mouse SCC tumor cells with 1α,25
(OH)2D3 elevated VDR expression and concurrently the
phosphorylation of ERK (extracellular signal-regulated
kinase) was inhibited. Upstream of ERK, cleavage of
the growth-promoting and pro-survival signaling
molecule MEK (kinase kinase) takes place and its
inactivation occurs in a caspase dependent manner in
cells that undergo apoptosis after treatment with
1α,25(OH)2D3. Lately, a novel mechanism of
1α,25(OH)2D3-mediated apoptosis in epithelial ovarian
cancer cells was proffered wherein they showed
telomerase reverse transcriptase (TERT) mRNA was
destabilized by 1α,25(OH)2D3, thus stimulating
apoptosis by telomere attrition ensuing from the down-
regulation of telomerase activity .
4.3. Role of Vitamin D in Cell Growth Regulation
VDR (vitamin D receptor) expression has been
revealed in various types of cultured human cell lines,
and regulation of proliferation of normal cell; including,
keratinocytes, prostate, breast, colon, kidney, pituitary,
thyroid, parathyroid, ovary, and myeloid precursors is
possible by 1α,25(OH)2D3. A G2/M cell cycle
progression is mediated by 1α,25(OH)2D3 and
induction of cell death in numerous cancer cell lines
through direct induction of GADD45 . GADD45α is
Fig. (2). Molecular basis of cancer and the modulation of cell fate .
Fig. (3). Calcitriol and cell cycle checkpoints .
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
of Cell Fate
Cell cycle arrest
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
Vit D role in Checkpoint G1/S
330 Current Molecular Medicine, 2017, Vol. 17, No. 5 Jain et al.
a DNA damage-induced and p53-regulated gene that
exerts an important role in cell cycle control and DNA
repair. Cell growth in normal and malignant cells is
inhibited by 1α,25(OH)2D3 by enhancing the expression
of either transforming growth factor- (TGF-) or its
receptors, which potently suppresses the proliferation
of many cells and is involved in control of cell cycle and
apoptosis . Whereas, the anti-proliferative functions
of VDR are related with arrest at the G0/G1 stage of
the cell cycle, coupled with upregulation of a number of
cell cycle inhibitors, including cyclin-dependent kinase
inhibitors p21(waf1/cip1) or p27(Kip1) and down-
regulation of p45SKP2 .
Experimental studies have depicted that
1,25(OH)2D3 suppresses human colonic cell and colon
cancer cell line proliferation . The number of MCF-7
cells in G1 were augmented by vitamin D3 compounds,
including 1,25(OH)2D3 and diminished the cells in S
phase. Cell cycle succession from G0/G1 to S and M is
regulated by growth-modulating stimuli from mitogens
and cyclin-dependent kinases (CDKs, a family of
nuclear protein kinases) . For the functional
activations of CDKs, their association with functional
subunits (cyclins) is required . Recent studies
reported that the up regulation of cyclin-dependent
kinase inhibitors (CDKIs), p21WAF1/CIP1 and p27kip1,
mediated the G1 arrest induced by 1,25(OH)2D3 in HL-
60 cells . In some cancer cell lines vitamin D3
compounds stimulated enhanced expression of
p27kip1 and p21WAF1/CIP1. These two CDKIs
appeared to be the most prominent regulator of VD
mediated G1 arrest . A principal feature of VD
induced p21WAF1/CIP1 action is that, this expression
is p53 tumor suppressor independent, which leads to
reinforcement of the postulation of direct regulation of
p21WAF1/CIP1 by VD. It was demonstrated by a
recent study that p21CIP1 and p27Kipl are inhibited by
CDK and it acts as molecular switches which alleviate
the vitamin D3 induced differentiation in leukemia cells.
Both of these genes were regulated by VD at
transcriptional level and post-transcriptional level
during the initial stages of the process. VD-induced p27
accumulation is the result of diminished degradation
which is supported by a number of evidences .
Ras gene mediates the proliferation-related activity
of VD and a large group of its analogs. Ras gene
shows mutation frequently in human cancer. Mutation
takes place in one of the three exons leading to an
amino acid substitution that alters the conformation of
Ras molecule, triggering its activity and its intrinsic
ability to turn off the molecular signal transduction from
cell membrane to the nucleus . Anchoring of the
Ras protein to the cell membrane is hastened by the
addition of a farnesyl moiety and this particular step,
which might be impeded by VD via competitive binding
. Vitamin D3seems to suppress malignant cell
transformation and alleviates the transit of regulatory
substances between carcinogen initiated and normal
cells by augmentation of gap-junction communication.
There is a rise in connexin-43 m-RNA with its increase.
This event relies on the role of nuclear VDR which
further suggests that 1,25(OH)2D3 modifies the
expression of endogenous genes in treated cells.
Prolonged exposure of cancer cells to increased levels
of 1,25(OH)2D3 changes the cell surface, thereby
making them targets of cytotoxic activity of murine and
human natural killer cells. It is one of the mechanisms
by which vitamin D3 delays the progression of human
cancer 1,25(OH)2 .
6. VITAMINS IN DIET: EFFECT ON CANCER
TREATMENT AND PREVENTION
Cancer constitutes the second major reason of
mortality in the United States. Currently used
anticancer drugs were discovered and developed using
chemotherapeutic agents as the base which was firstly
used for cancer treatment in 20th century. Most of the
chemotherapeutic agents can shrink the size of tumor
to a large extent but, they often fail in extirpating
tumors. Finally, drug resistance and recurrence may be
developed by cancer. Recently, a lot of research has
shown the presence of cancer stem cells (CSCs) or
tumor-initiating cells (TICs) in certain human cancers.
Nevertheless, the recently existing treatment
approaches, including chemotherapy and radiotherapy,
are incapable of effectively killing these CSCs. Thus,
these CSCs are at present a target for cancer
prevention and its treatment. Because numerous
epidemiological studies have proved a relation between
consumption of fruits and vegetables and the lowered
risk of several cancers, naturally existing dietary
compounds have sought heed for being efficacious in
cancer chemoprevention . The anticancer effects of
various dietary compounds have been accounted in
vitro and in vivo studies. Various in vitro studies and
animal experiments give evidence regarding the
biochemical and molecular modes of action for certain
nutrients which aid in assessing the functions of dietary
supplements in cancer prevention. Observational
researches conducted in human populations provide
evidence which might also be raised in favor of an
intended relation between a nutrient and a cancer
outcome. This evidence could provide the rationale for
testing of experiments in humans, usually through a
randomized controlled trial (RCT) which is considered
as the “gold standard” .
The major carotenoids which show vitamin A activity
in human plasma are β-carotene and β-cryptoxanthin,
while the major carotenoids without vitamin A activity
are lutein, lycopene and zeaxanthin. Epidemiological
studies have shown the preventive effect of vitamin A
intake on bladder cancer. The risk approximations of
bladder cancer were found to be 0.82 (95% CI 0.65,
0.95) for total vitamin A intake, 0.88 (95% CI 0.73,
1.02) for retinol intake, and 0.64 (95% CI 0.38, 0.90) for
blood retinol levels . Meta-analysis demonstrated
that high vitamin A intake was linked with a reduced
risk of bladder cancer .
β-carotene is a carotenoid that undergoes
conversion to vitamin A in the gut. A high dose of β-
carotene causes an elevated risk of lung cancer and
Vitamins for Cancer Prevention and Treatment: An Insight Current Molecular Medicine, 2017, Vol. 17, No. 5 331
all-cause mortality amongst smokers . It was
depicted in intervention trials that β-carotene
supplements at pharmacological doses did not protect
against lung cancer in comparison to placebo. Instead
supplemental β-carotene led to a modest elevation in
lung cancer risk amidst heavy smokers and asbestos
workers. Though an inverse association has been
found between β-carotene at dietary level and lung
cancer risk in few studies of epidemiology, the current
evidence is consistently depicting a benefit in more
consumption of fruits and vegetables . Therefore,
β-carotene might indicate different bioactives present in
food rather than being responsible for the various
inverse associations found between the consumption of
fruits, vegetables and lung cancer . In three cohort
studies, no elevation in risk of prostate cancer (PC)
was observed with 25 mg/day and there occurred a
lowering in risk for those with low levels of lycopene in
plasma. In one study, intake above 20 mg/day (only 40
mg/2 days) led to an elevated risk of PC . β-
carotene was also related with an elevated risk of
aggressive PC . Dietary carotenoids are provided
solely from fruits and vegetables. Carotenoids act as
potent antioxidants and have also been found to
regulate cell growth and induce apoptosis; some
carotenoids may serve as precursors of vitamin A. β-
carotene and lycopene are the most studied
carotenoids with regard to prostate cancer .
Various studies have been performed on β-carotene
and prostate cancer. Out of these, two intervention
studies, one found no effect of β-carotene on prostate
cancer; whereas the other, the ATBC study, depicted
that β-carotene supplementation led to a 23% elevation
in occurrence of and 15% elevation in mortality from
prostate cancer. Nevertheless, β-carotene did not show
any effect on the post intervention follow-up .
Taking into consideration that prostate cancer
incidence and mortality were not the main endpoints of
the ATBC, and that other studies do not depict a
damaging effect due to β-carotene, these research
findings may be haphazard. One prospective study and
3 case control studies found a protective effect of β-
carotene, whereas 6 other case-control studies and 1
prospective study found no outcome. In a few
analyses, other carotenoids pose an increased risk of
prostate cancer. McCann et al. (2005) demonstrated
that high intakes of α -carotene (OR = 0.67; 95% CI,
0.47–0.97) and lutein (OR = 0.55; 95% CI, 0.37–0.81)
were related with a reduced risk of prostate cancer.
Nevertheless, associations between prostate cancer
risk and individual carotenoids were weakened after
moderating the vegetable intake . Schuurman et
al. (1999) evinced that β-cryptoxanthin was positively
linked with prostate cancer risk, whereas other
carotenoids did not show any association with risk.
Randomized trials of β-carotene do not distinctly
manifest any advantageous effect on prostate cancer.
Prospective studies depict a potentially beneficial effect
of carotenoids, peculiarly lycopene, on prostate cancer
risk. Few clinical trials have demonstrated interesting
outcomes, especially with lycopene, but these studies
are of small sample size and relatively brief in duration
6.2. Vitamin E
Although γ-tocopherol is the most abundantly found
form of vitamin E in the U.S. diet; yet, study has been
conducted on α-tocopherol because, it is the biolo-
gically prevalent form in humans and most commonly
employed in supplements . γ-tocopherol was
found to act by inhibition of the proliferation of LNCaP
and PC-3 prostate cancer cells by interference in the
de novo synthesis of sphingolipids, while not affecting
normal prostate epithelial cells. Due to its intracellular
antioxidant action Vitamin E may aid in the prevention
of cancer . The focus of most of the studies has
been on vitamin E in the form of α-tocopherol; two
studies measuring γ-tocopherol demonstrated an
inverse relation with prostate cancer risk. Recently, in a
mouse prostate model, hypermethylation of CpG
sequences in the Nrf2 promoter region in the
transgenic adenocarcinoma has been prevented by γ-
tocopherol thus aiding to safeguard against oxidative
stress and in prevention of prostate tumorigenesis. In
one other study the anticancerous activity and mode of
action of a γ-tocopherol-rich tocopherol mixture, γ-TmT
was evaluated in two varying animal models of
estrogen-induced breast cancer. The chemopreventive
effect of γ-TmT at early (6 weeks), intermediate (18
weeks), and late (31 weeks) stages of mammary
tumorigenesis was found out with the help of the
August-Copenhagen Irish rat model. Mammary tumor
development was reduced by γ-TmT by lowered E2
availability and reduced oxidative stress in mammary
tissues; thus, γ-TmT could be an effective agent in the
prevention and treatment of E2-induced breast cancer
. All these findings show that all forms of vitamin E
are not similar with respect to prostate cancer but, α-
tocopherol may be detrimental. Vitamin E acts as an
antiprostaglandin; whereby prostaglandins are
considered to possess a role in PC. The effectiveness
of γT and a mixture of tocopherols against colitis and
colitis-promoted colon tumorigenesis was investigated
in male BALB/c mice . It depicted that γT was
capable of alleviating moderate but not severe colitis
and it elevated tumorigenesis, and demonstrated that
inflammation severity needs to be looked at while
evaluating anticancerous effectiveness of
chemoprevention agents . The consequences of a
preparation of aγ-tocopherol-rich mixture of tocopherols
(γ-TmT) on chemically induced lung tumorigenesis in
female A/J mice and the growth of H1299 human lung
cancer cell xenograft tumors were investigated. Dietary
0.3% γ-TmT treatment during the whole experiment
significantly reduced tumor multiplicity, tumor volume
and tumor burden (by 30, 50 and 55%, respectively; P
< 0.05). The results revealed the inhibitory effect of γ-
TmT against lung tumorigenesis and the growth of
xenograft tumors of human lung cancer cells. Over
consumption of vitamins and minerals may be
associated with side effects . A lowered risk was
found in vitamin E intake when studies were conducted
in a three case–control and one cohort study. A higher
332 Current Molecular Medicine, 2017, Vol. 17, No. 5 Jain et al.
consumption of vitamin E was related with a reduced
risk of advanced PC as observed in a large cohort
study. However, in four cohort studies impact was
observed for vitamin E consumption and three case-
control studies. A total six cohort studies were
examined by the WCRF/AICR expert panel, 14 case-
control studies and an ecological study related to
dietary/serum vitamin E, which led to a conclusion that
there exists a ‘probable’ relation between intake of
vitamin E and a lowering in the risk of PC. Vitamin E
intake of over 400 IU was observed to elevate all-cause
mortality. All these data depict that vitamin E
supplements may lower the risk of PC, especially in
smokers and in those with low serum levels;
howsoever, a high vitamin E consumption may be
detrimental . Recent trial of the Selenium and
Vitamin E Cancer Prevention (SELECT) showed that
an increased prostate cancer incidence was found in
men getting solely the vitamin E supplement . But,
there occurred no increase in its incidence in men
receiving both vitamin E and selenium, concluding that
the two nutrients may influence prostate cancer risk by
their interactive mechanisms. The baseline levels of
oxidative stress may influence the effect of vitamin E
since; a lowered risk of prostate cancer has been found
with elevating dose and duration of vitamin E
supplementation in various current and recent smokers
. Though few evidences about vitamin E and
prostate cancer are inconsistent, the most of the
studies indicate that vitamin E does not decrease
prostate cancer risk .
6.3. Folic Acid
Folate which is a water soluble B vitamin is needed
for numerous methylation-related processes. The terms
“folate” and “folic acid” may be used as synonyms
certain times, the latter is the synthetic oxidized form
which is generally used in fortification and
supplements, while naturally existing folates are
reduced molecules existing in nature in various forms
with varying degrees of polyglutamation [111, 112]. In
regard to colorectal neoplasia, the folate and folic acid
association with the risk of cancer has been studied
meticulously . Despite being proposed that more
protection may be provided by the synthetic forms as
compared to the natural forms of folate, outcomes of a
meta-analysis of observational studies of colorectal
cancer depicted that no greater protection was
conferred by total folate (dietary plus synthetic sources)
when compared with dietary folate. Recently, a meta-
analysis of a randomized controlled trial (RCTs)
observed no impact of supplementation of folic acid on
colorectal adenomas risk over the treatment period of 3
years, which was in contrast to the data observed
which depicted a protective relation between folate
status and the risk . The outcomes of one trial
revealed that long-term supplementation of folic acid
raised the risk of advanced colorectal adenomas
(relative risk = 1.67; 95% confidence interval = 1.00 to
2.80) and developed three or more adenomas (relative
risk = 2.32; 95% confidence interval = 1.23 to 4.35). An
increased risk of prostate cancer was also found in this
RCT. A high breast cancer risk has been reported
among individuals consuming high folic acid; various
studies have associated a large dietary intake and high
folate concentration in circulation with an elevated
prostate cancer risk . The effect of dietary folate
manipulation on prostate cancer progression was
determined. Mild dietary folate depletion arrested
prostate cancer progression in 25 of 26 transgenic
adenoma of the mouse prostate (TRAMP) mice, in
which tumorigenesis is prostate-specific. The
substantial effect on prostate cancer growth was
characterized by size, proliferation, and apoptosis
analyses. Supplementation of folate had a mild, non-
significant and beneficial effect on grade. In addition,
characterization of folate pools (correlated with serum),
metabolite pools (polyamines and nucleotides), genetic
damage, and expression of key biosynthetic enzymes
in prostate tissue showed correlations with tumor
progression . It suggested that antifolates, paired
with existing strategies, may remarkably enhance the
treatment of prostate cancer . A study was
performed to assess the relation between vitamin C, E,
folate and beta-carotene and lung cancer risk while
concentrating on the source-specific consequences of
dietary and supplemental intake. During a follow-up of
10.6 years, 721 incident lung cancer cases were
detected. The three micronutrients (i.e. vitamins C, E,
and folate) exhibited significant source-specific effects.
It indicated source-specific effects of vitamin E and
beta-carotene in lung cancer prevention with a
preventive effect of dietary vitamin E and a deleterious
effect of supplemental beta-carotene . A total of
399 incident colon cancers accessible for p53
expression were taken into consideration. The effect of
folate varied importantly according to p53 expression
[P (heterogeneity) = 0.01]. In comparison to women
reporting folate intake <200 µg/day, the multivariate
relative risks (RRs) for p53-overexpressing (mutated)
cancers were 0.54 (95% confidence interval [CI], 0.36-
0.81) for women who consumed 200-299 µg/day, 0.42
(95% CI, 0.24-0.76) for women who consumed 300-
399 µg/day, and 0.54 (95% CI, 0.35-0.83) for women
who consumed >or=400 µg/day. In contrast, total folate
intake had no influence on wild-type tumors (RR, 1.05;
95% CI, 0.73-1.51; comparing >or=400 with <200
µg/day). Similarly, high vitamin B (6) intake conferred a
protective effect on p53-overexpressing cancers [top
versus bottom quintile: RR, 0.57; 95% CI, 0.35-0.94; P
(heterogeneity) = 0.01] but had no effect on p53 wild-
type tumors. It was observed that low folate and
vitamin B (6) intake was associated with an elevated
risk of p53-overexpressing colon cancers but not wild-
type tumors [118, 119].
6.4. Vitamin D
A great interest has been created by vitamin D for
cancer prevention, especially in concern to breast,
colorectal, and prostate cancers . Since the RCTs
of vitamin D are comparatively sparse, current
assessments of potential harm from this nutrient must
currently depend on observational data. On the basis of
a report obtained from a large observational study,
Vitamins for Cancer Prevention and Treatment: An Insight Current Molecular Medicine, 2017, Vol. 17, No. 5 333
there was concern regarding an association between
high vitamin D concentrations and pancreatic cancer;
however, a recent meta-analysis depicted that higher
concentrations were associated with a decrease in risk
. With respect to prostate cancer, a recent study
demonstrated a statistically remarkable elevated risk
for prostate cancer among men with the highest
concentrations of 25(OH) D .
Chemoprevention was evaluated in a mouse model
of tobacco carcinogen-induced bladder tumors using
60 A/J mice which were randomized to normal diet, low
calcium diet, and diet with chemoprevention (acetyl
salicylic acid, 1-alpha 25(OH)2-vitamin D3 and calcium).
There were remarkably fewer tumors (0 (0-0) vs. 0 (0-
2), p = 0.045) and fewer animals with tumors (0/20 vs.
5/20, p = 0.045) in the chemoprevention group in
comparison with controls. Therefore, chemoprevention
diet effectively decreased the tumor promoting effect of
tobacco carcinogens in the mouse bladder . A
case control study was conducted to assess the
association between dietary calcium and vitamin D
intake and cervical neoplasia risk. 405 incident cervical
neoplasias (333 invasive carcinomas and 72 cervical
intraepithelial neoplasias grade III (CIN3)) and 2025
age-matched non-cancer controls were selected.
Compared with the lowest quartile (Q1) of calcium
intake, adjusted odds ratios (ORs) for each of the three
upper quartiles (Q2, Q3 and Q4) on invasive carcinoma
risk were 0.86 (95% confidence interval (CI) 0.63-1.17),
0.50 (95% CI 0.34-0.73) and 0.68 (95% CI 0.48-0.97),
respectively (P for trend=0.004). Although no
association between calcium and cancer risk was seen
among CIN3 cases (P for trend=0.528). Vitamin D
intake revealed a similar inverse association (Q2: OR
1.03, 95% CI 0.74-1.44; Q3: OR 0.80, 95% CI 0.56-
1.15; and Q4: OR 0.64, 95% CI 0.43-0.94; P for
trend=0.013). Similar to calcium, no association
between vitamin D intake among CIN3 was evident (P
for trend=0.109). An inverse association with calcium
was found in women with low vitamin D intake .
Vitamin D3 has been depicted to decrease the
occurrence of human breast, prostate and colon
cancers and induces apoptosis and cell cycle arrest of
various cancer cell types. Palmer et al. (2001)
manifested that vitamin D3 stimulated the
differentiation of colon carcinoma cells by the induction
of E-cadherin expression and the suppression of β-
catenin signaling . Ligand-activated vitamin D
receptor competed with TCF-4 for β-catenin binding,
thereby decreasing the levels of c-Myc, peroxisome
proliferator-activated receptor, TCF-1 and CD44 . A
study was conducted in order to establish a relationship
between increasing vitamin D intake on development of
preneoplastic lesions in the colon of mice, serum 25-
hydroxyvitamin D3 (25-D3) levels, and expression of
renal vitamin D system genes. Dietary vitamin D
concentration was found to correlate inversely with
dysplasia score (Spearman's correlation coefficient, ρ: -
0.579, p=0.002) and positively with serum 25-D3 levels
(ρ: 0.752, p=0.001). Raising dietary vitamin D
concentration beyond 1000IU/kg led to no further rise
in circulating 25-D3 levels, while the dysplasia score
leveled out at ≥2500IU/kg vitamin D. A high dietary
vitamin D intake led to elevated renal mRNA
expression of the vitamin D catabolizing enzyme
cyp24a1 (ρ: 0.518, p=0.005) and reduced expression
of the vitamin D activating enzyme cyp27b1 (ρ: -0.452,
p=0.016). It depicted that increasing dietary vitamin D
intake is able to prevent chemically induced
preneoplastic lesions .
6.5. Vitamin C
Vitamin C inhibits oxidative damage to cells by
scavenging free radicals, recycles vitamin E (α-
tocopherol), and prevents the growth and viability of
prostate cancer cells. However, only 1 intervention, 2
prospective and 3 case control studies of dietary or
supplemental vitamin C and prostate cancer have been
reported. Of these, 2 case control studies reported
decreased prostate cancer risk associated with vitamin
C intake, whereas other reported studies did not depict
any relation. A risk of head and neck cancer (HNC)
was reported when vitamin C and carotenoid is taken in
diet. Intake of dietary vitamins C and E and carotenoids
(α-carotene, β-carotene, and lycopene, etc.) was
studied in a cohort design. After 20.3 years of follow-
up, 3898 subcohort members and 415 HNC cases (131
oral cavity cancer (OCCs), 88 oro-/hypopharyngeal
cancer (OHPs), and 193 laryngeal cancer cases) were
available for analysis. An inverse relation was
demonstrated between vitamin C and HNC .
A comprehensive meta-analysis was performed to
test the hypothesis that a high intake of vitamin C has a
protective effect on glioma risk. The combined relative
risks (RRs) of glioma associated with vitamin C intake
was found to be 0.86 (95% CIs = 0.75-0.99). Overall,
significant protective associations were also found in
the American population (RRs = 0.85, 95% CIs = 0.73-
0.98) and case-control studies (RRs = 0.80, 95% CIs =
0.69-0.93). The results showed that intake of vitamin C
may reduce the risk of glioma among the Americans
. The study by McCann et al. discovered that the
effect of vitamin C was weakened after adjusting total
vegetable intake, while another study did not make any
adjustments. Therefore, it appeared likely that vitamin
C does not affect prostate cancer risk, but instead it
may indicate vegetable intake . Effect of vitamin C
on growth of experimental endometriotic cysts was
investigated. The cyst volume in Group V3 and the cyst
weights in Groups V2 and V3 were importantly lower
than those in Group C. There was a significant
reduction in the volumes and weights of the
endometriotic cysts with a dose-dependent vitamin C
supplementation . Cha et al. (2013) conducted a
study to ascertain the effect of ascorbate
supplementation on metastasis, tumor growth and
tumor immunohistochemistry in mice which were
incapable in synthesizing ascorbic acid [gulonolactone
oxidase (gulo) knockout (KO)] specifically in case of
B16FO melanoma or 4T1 breast cancer cells.
Ascorbate-supplemented gulo KO mice injected with
B16FO melanoma cells revealed remarkable reduction
(by 71%, p=0.005) in tumor metastasis when compared
334 Current Molecular Medicine, 2017, Vol. 17, No. 5 Jain et al.
to KO mice on the control diet. The mean tumor weight
in ascorbate supplemented mice injected with 4T1 cells
was found to reduce by 28% compared to tumor weight
in scorbutic mice. It was revealed that ascorbate
supplementation hinders metastasis, tumor growth and
inflammatory cytokine secretion as well as enhanced
encapsulation of tumors elicited by melanoma and
breast cancer cell challenge in gulo KO mice .
7. PHARMACEUTICAL ROLE OF VITAMINS IN
Commercial varieties of vitamin formulations are
available to treat the deficiency. Cancer, life
threatening disease causes serious illness worldwide
. From past few decades, the role of vitamins is
emerged in the field of cancer therapy, mostly vitamin
A, D and E. Treatment of cancer through anticancer
medication is a common phenomenon. The biggest
demerit of chemotherapy is destroying healthy tissue in
association with tumorous tissues resulting to
impairment of various vital organs like bone marrow,
liver, and GIT, etc. [131, 132]. Therefore, drug efficacy
and patient compliance towards disease and toxicity is
an important aspect that has to be considered.
Nanomedicines potentially elaborate the harmful
aspects of conventional chemotherapy either restricted
to target non-healthy tissue or deliver the medication to
the desired target site [133-135]. Enhanced
permeability and retention effect (EPR) makes the
nanomedicines as the most potent and efficient way to
target tumors via delivery of nano-vectorized
medication (Fig. 4) .
Abnormal basement membrane and inner linings of
endothelial makes the tumor vessels leaky in nature
and it facilitates the nanomedicines to target the tumor
site via leaky vasculature passively [130, 136, 137].
Nanocarriers overcome the immune surveillance by
using EPR effect and improve their circulation for
prolonged time. Various aspects are importantly
considered such as size, surface behavior and immune
blindness of nanoparticle to reach the desired aim. The
diameter of particle do not deviate from the range of
20–300 nm for the effectively extravasate in leaky
vesicles . To overcome the problem of clearance
via first pass renal filtration, the diameter of
nanocarriers must be larger.
Fig. (4). Passive and active targeting strategies of nanocarriers (Vitamin ligand coupled to nanocarriers binds to the receptors
overexpressed onto tumor or angiogenic endothelial cells).
Vitamins for Cancer Prevention and Treatment: An Insight Current Molecular Medicine, 2017, Vol. 17, No. 5 335
Fig. (5). Schematic representation of targeting potential of vitamin pioneered drug/bioactive or nanocarrier.
Neutral or anionic charge facilitates the renal
elimination effectively. Concept of PEGylation makes
the nanocarriers free from RES uptake via
phagocytosis or opsonization . Interstitial fluid
pressure must be high and blood flow should be
heterogeneous and the degree of tumor vascularization
and angiogenesis are the key factor to enhance the
effectiveness of passive targeting . Attachment of
ligands at the nanomedicines surface tremendously
improves the targeting with the facilitation of active
targeting to those receptors which are overexpressed
due to tumor (Fig. 5) . Controlled drug release
profile kinetics, prolonged circulation of drug, and
improved patient compliance are safely possible by the
potential use of nanomedicines. Nanomedicines also
bypass the toxicity of incorporated additives and
potentially overcome the resistance problem in
chemotherapy. Nanomedicines are a very effective
approach for combination therapy which limits the low
bioavailability issues. Nanomedicines combine
therapeutic and imaging agents to be safely employed
for treatment and diagnosis of disease [141, 142].
Tocopherols (vitamin-E) evolved as a great
therapeutic effectiveness to prevent the wide variety of
life threatening diseases i.e. heart diseases, cancer,
and also very helpful in Alzheimer's disorder [143-146].
Application of vitamin-E analogs as anti-cancer drugs
and anticancer adjuvants is elaborated in this portion
namely TOS (tocopheryl succinate) and TPGS (D-α-
Tocopherol polyethylene glycol succinate). Applications
and important characteristics of anticancer drug
delivery for TOS and TPGS are explained in this part
(Table 4) .
336 Current Molecular Medicine, 2017, Vol. 17, No. 5 Jain et al.
Table 4. Vitamin E-based nanomedicines for anticancer drug delivery.
Model for the Study
Breast and uterine cancer
In vitro and in vivo
In vitro and in vivo
In vitro and in vivo
TOS modiﬁed pluronic
In vitro and in vivo
Breast and MDR cancer
Breast and MDR cancer
In vitro and in vivo
DOC and QDs
In vitro and in vivo
Breast and melanoma
In vitro and in vivo
In vitro and in vivo
PTX and shRNA
Lung and breast cancer
In vitro and in vivo
In vitro and in vivo
TPGS + 4-armed
TPGS + MPEG-SS-PLA
Lung, breast and uterus
FOL–TPGS and DOX–
In vitro and in vivo
In vitro and in vivo
Hepatocarcinoma In vitro
Cisplatin, DOC and
Abbreviation: PK, pharmacokinetics; PTX, paclitaxel; DOX, doxorubicin; PEG-PE, poly(ethylene glycol)-phosphatidyl ethanolamine; PEG-DSPE, 1,2-distearoyl-sn-
glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)]; CPT, camptothecin; PLV(2K) lysine-linked di-tocopherol polyethylene glycol 2000 succinate; DOC,
docetaxel; QDs, quantum dots; NSCLC, non-small cell lung cancer; PLA, poly-lactic acid; PLGA, poly (lactic-co-glycolic acid); FOL, folic acid, MDR, Multi Drug
CANCER IS THE CONCLUSION
major reason of death in the United States and
researches depict that most of these could be averted
by various dietary factors influencing the cellular
environment. Epidemiological, preclinical, and clinical
studies furnish a support for the hypothesis that
vitamins like vitamin D and vitamin A have a substantial
protective action against cellular transformation which
leads to cancer whereas the anticancer activities of
vitamins B, C, E and K are quite limited. The promising
benefits of vitamins in cancer prevention and treatment
may be achieved by employing new potent analogs as
well as combinations of vitamins in the early stages of
cancer. There is still need to quest the roles of vitamins
in cancer in terms of synergistic, antagonistic, and
potentiating activity against cancer. Even dosing of
Vitamins for Cancer Prevention and Treatment: An Insight Current Molecular Medicine, 2017, Vol. 17, No. 5 337
vitamin is questionable due to various dosage
regimens of chemotherapy and phototherapy. Vitamin
as a ligand to facilitate targeted drug or gene delivery
to selective tumor is under extensive exploration.
Oncologists and budding scientists are trying to resolve
brain teasing query “how do vitamins act as nutrients or
poisons to tumor cells?”
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial
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