ArticlePDF Available

Abstract and Figures

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.
Content may be subject to copyright.
Send Orders for Reprints to reprints@benthamscience.ae
Current Molecular Medicine 2017, 17, 321-340 321
REVIEW ARTICLE
1566-5240/17 $58.00+.00 © 2017 Bentham Science Publishers
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
DOI:
10.2174/1566524018666171205113329
Keywords: Vitamin, cancer, prevention, treatment, diet, metabolism, targeting.
1. INTRODUCTION
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 [1]. 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: drskjainin@yahoo.com
(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
vitamins, respectively.
2. VITAMINS AND THEIR ANALOGS FOR
CANCER TREATMENT
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 [37]. 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 [25]. Cancer is a serious disease
in which mortality rates of patients have been
increasing per year [38]. About one sixth of all deaths
have been accounted due to cancer in the United
States and many other developed countries [39]. 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.
Chemical
Name or
Common
Name
Source or
Synthesis
Basic Ring
Daily
Requirement
Deficiency
Cause
Toxicity
Ref.
Vitamin A
Carrot,
mangoes,
papaya, green
leafy vegetable,
and fish liver oil
β-ionone
ring (p-
ionone
derivatives
with retinol
activity)
RDA for adults
is 1000 RE for
males and
800 RE for
females [7]
Night
blindness,
xerophthal-
mia,
keratomalacia
and
keratinisation
of epithelium
Dry,
headache,
itchy skin,
nausea, loss
of appetite,
dizziness,
blurred vision
and slowed
growth. Its
toxicity also
can cause
severe birth
defects and
may elevate
the risk for hip
fractures.
[7-
10]
Vitamin D (pro-
hormone);
1,25-dihydroxy
cholecalciferol
Synthesize from
7-dehydro
cholesterol in
the malpighian
layer of
epidermis, by
the action of
ultra violet rays
Steroid
5-10 µg
Rickets in
children and
osteomalaci
a in adults.
High doses
may lead to
accumulations
in the liver and
develop signs
of poisoning,
poor mental
and physical
growth,
reduced
appetite,
nausea and
vomiting.
[7,
11-
13]
Vitamin E;
Alpha
tocopherol
Vegetable oils
are rich sources
of Vitamin E,
e.g. wheat germ
oil, sunflower
oil, safflower oil,
cotton seed oil,
and palm oil
6-hydroxy
chromane
(tocol) ring
5 mg (7.5 IU) /
day and an
additional 0.6
mg for each
gram of
polyunsaturated
fatty acid
consumed may
be sufficient
Sterility,
degenerativ
e changes,
alterations in
central
nervous
system
No significant
toxicity
[14-
17]
Vitamin K;
K1:
phylloquinone
and
K2:
menaquinones
(Menadione is
synthetic water
soluble Vitamin
K)
Bacteria in the
gastrointestinal
tract naturally
make vitamin K.
Green leafy
vegetables:
collards, green
leaf lettuce,
kale, mustard
greens, parsley,
romaine lettuce,
spinach, Swiss
chard and turnip
greens as well
as vegetables
such as
broccoli,
Brussels
sprouts,
cauliflower and
cabbage [18].
Naphthoqui
none
30 µg/ day
The blood
clotting time
is increased
Breakdown of
red blood cells
and liver
damage
[19,
20]
Vitamins for Cancer Prevention and Treatment: An Insight Current Molecular Medicine, 2017, Vol. 17, No. 5 323
Table 2. Various water soluble vitamins.
Vitamin;
Chemical
Name or
Common
Name
Source or
Synthesis
Basic Ring
Co-Enzyme
Daily
Requirement
Biological Role
Deficiency Cause
Toxicity
Ref.
Vitamin B1,
Thiamine (The
active form of
vitamin B1 is
thiamine
diphosphate)
Aleurone layer of
cereals (food
grains), Whole
wheat flour and
unpolished rice
and yeast
Pyrimidine
ring and a
thiazole
ring held by a
methylene
bridge
Thiamine
Pyrophosphat
e (TPP)
1 to 1.5 mg
Transketolase is TPP
dependent in HMP shunt
pathway. Enzyme pyruvate
dehydrogenase catalyses
(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
acids.
Beri-beri,
polyneuritis and
Wernicke-Korsakoff
syndrome
No toxicity
[21]
Vitamin B2
Riboflavin
Liver, dried yeast,
egg, and milk
Isoalloxazine
ring attached
to D- ribitol by
a nitrogen
atom.
Flavin
mononucleotid
e (FMN) and
flavin adenine
dinucleotide
(FAD)
1.5 mg per
day
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.
Succinate dehydrogenase,
acyl CoA dehydrogenase,
xanthine oxidase, glutathione
reductase, glycine cleavage
system, pyruvate
dehydrogenase, and alpha
ketoglutaratedehydrogenase).
Glossitis, cheilosis,
angular stomatits,
and
Circumcornealvascul
arisation
No toxicity
[22]
Vitamin B3
Niacin
(nicotinic acid/
nicotinamide)
Dried yeast, rice
polishing, liver,
peanut, whole
cereals, legumes,
meat and fish.
About half of the
requirement is
met by the
conversion of
tryptophan to
niacin. (About 60
mg of tryptophan
will yield 1 mg of
niacin) [23]
Pyridine
Derivative
Nicotinamide
adenine
dinucleotide
(NAD)
and
nicotinamide
adenine
dinucleotide
phosphate
(NADP)
7.5 mg/day
The coenzymes NAD and
NADP are involved in a variety
of oxidation-reduction
reactions.
NADH produced is oxidized in
the electron transport chain for
generation of ATP. [Lactate
dehydrogenase,
glyceraldehyde-3- phosphate
dehydrogenase, pyruvate
dehydrogenase, beta hydroxy
acyl CoA dehydrogenase, and
mitochondrial isocitrate
dehydrogenase are NAD
dependent enzymes].
Pellagra with
diarrhoea, dermatitis
, and
Dementia
Consuming
large doses
of niacin
supplements
may cause
flushed skin,
rashes or
liver damage
[24]
Vitamin B5;
Panthothenic
Acid
Animal tissues,
whole-grain
cereals, and
legumes; widely
distributed
Pantoic acid
and β-
alanine,
held together
by a peptide
linkage
Co-enzyme
A (CoA)
10-15 mg/day
0.8 mg/day
Coenzyme A acts as a carrier
of activated acetyl or acyl
groups. It is a central molecule
which is involved in all the
metabolisms (carbohydrate,
lipid and protein)
Burning feet
syndrome
(Pain and numbness
in the toes,
sleeplessness,
fatigue, etc.)
No toxicity.
Rarely,
diarrhea and
water
retention.
[25]
Vitamin B6;
pyridoxine,
pyridoxamine
and pyridoxal
Yeast, rice
polishing, wheat
germs, cereals,
legumes (pulses),
egg, milk, meat,
fish and green
leafy vegetables
[26]
Pyridine
Pyridoxal
Phosphate
(PLP)
1.5-2 mg/day;
0.4 mg/day
for infants
Transamination reactions,
decarboxylation of amino
acids, ALA synthase, glycogen
phosphorylase
Infantile convulsions,
peripheral neuritis
(neurological
symptoms), pellagra
(PLP deficiency in
turn leads to niacin
deficiency),
anaemia, reduced
synthesis of
biogenic amines
serotonin, GABA,
norepinephrine and
epinephrine
Rare toxicity
but at higher
dose may
cause nerve
damage
[19,
27]
(Table 2) Contd.
324 Current Molecular Medicine, 2017, Vol. 17, No. 5 Jain et al.
Vitamin;
Chemical
Name or
Common
Name
Source or
Synthesis
Basic Ring
Co-Enzyme
Daily
Requirement
Biological Role
Deficiency Cause
Toxicity
Ref.
Vitamin B7 or
H; Biotin
Liver, yeast,
egg, yolk, soy
flour and
cereals (also
synthesized
by the
intestinal
flora)
Fusion of
imidazole and
thiophene
rings
Biotin (Vitamin H
or B7)
2.5 mg/day
Biotin functions as a carrier of
CO2 in carboxylation reactions
(Acetyl CoA carboxylase,
propionyl CoA carboxylase,
and pyruvate carboxylase
reactions).
Biotin-avidin reaction is used
in immunosorbent assays.
Anemia, loss of
appetite, nausea,
dermatitis glossitis
No toxicity
[28]
Vitamin B9;
Folic acid
Yeast, liver,
egg, green
leafy
vegetables,
cereals,
and pulses
Components
pteridine ring,
p- amino
benzoic
acid (PABA)
and
glutamic acid
Tetrahydrofolic
acid (THFA)
200 mg/day.
In pregnancy,
the
requirement is
increased up
to 400
mg/day.
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.
Pregnancy,
defective absorption
(sprue, celiac
disease),
anticonvulsant drugs
(hydantoin, dilantin,
phenytoin,
phenobarbitone),
haemolyticanaemias
(Macrocytic
anaemia) and
dietary deficiency
No toxicity
[29]
Vitamin B12;
Cyanocobalami
ne
Meat,
shellfish, fish,
milk, eggs
The corrin
ring has four
pyrrole units,
just like a
porphyrin
Methylcobalamine
;
Deoxyadenosylco
balamine
2 µg/per day
Isomerization of methymalonyl
CoA to succinyl CoA.
Synthesis of methionine from
homocysteine.
Methyl
malonicaciduria,
accumulation of
methyl malonic acid,
breakdown of myelin
sheaths and
interruption in nerve
transmission.
Homocysteinuria is
also seen.
Pernicious anaemia.
No toxicity
[30-
32]
Vitamin C
L-ascorbic acid
Plant foods
contain
vitamin C; the
best sources
are citrus
fruits (orange,
kiwi fruit,
grape, etc.)
Resembles
Monosacchari
des
Vitamin C
50200
mg/day
Collagen formation, bone
formation, and metabolism of
tryptophan, tyrosine, heme,
haemoglobin and folic acid
Scurvy (hemorrhagic
tendency, microcytic
anemia, bone pain,
bleeding gums)
Overdoses
may cause
kidney
stones, gout,
diarrhea and
rebound
scurvy
[33,
34]
Vitamin P; rutin
and hesperidin
or bioflavonoids
Lemons,
grapefruits,
oranges, lime,
grapes,
cherries,
plums,
peaches,
apricots,
apples,
berries,
vegetables
such as green
and yellow
peppers,
tomatoes,
onions,
broccoli,
parsley.
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-
inflammatory properties.
Inhibits the cancer growth thus
useful in treating tumors.
Decreases the chances of
cardiovascular diseases.
Easy bruising,
exuberant swelling
after injury, like
sports injuries, nose
bleeds, hemorrhoids
or varicose veins
and weak immune
system, leading to
frequent colds or
infections
No toxicity
[35,
36]
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-
45].
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 [46]. 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 [47].
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 [48]. 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 [49].
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 [50]. 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 [51]. 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 [48].
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 [45].
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 [52]. Vitamin C majorly works as an
antioxidant and free radical scavenger and plays an
essential role in collagen synthesis [53]. 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 [54]. 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
placebo [55].
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 [56]. 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 [57]. Clinical
trials using EB-1089 are currently being investigated for
the treatment of breast cancer [58].
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
[59]. 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 [60]. Table 3
summarizes different types of vitamins and their
anticancer activity.
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 [69].
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 [70]. 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 [49].
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 [49].
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
sunlightvitamin 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 ml1 (130 nmol
liter1). 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 [65].
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 [73].
5. MECHANISMS OF ANTICANCER ACTIONS
OF VITAMINS
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 [74]. 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
Anticancer Activity
Ref.
Vitamin A
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]
Vitamin C
Prostate
[63]
Vitamin D
Breast, melanoma, colon, ovarian, pancreatic cancer, Hodgkin’s lymphoma.
[58, 64, 65]
Vitamin E
Prostate
[66-68]
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 ECMpermitting them the access to lymph or blood
vessels and to metastasize [75].
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 [73].
4.1. Role of Calcitriol (Vitamin D) in Cell Division
Regulation
Due to its role in controlling the cell cycle, calcitriol
shows protective effects against cancer development
[76]. 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 [77]. 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) [73]. 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 [64]. 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 [78]. 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/Scdk and
Scdk activities.
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) [79]. It has been
demonstrated that BCL2 expression in MCF7 breast
tumor and HL60 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 [80]. 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 [81].
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 [82]. GADD45α is
Fig. (2). Molecular basis of cancer and the modulation of cell fate [73].
Fig. (3). Calcitriol and cell cycle checkpoints [73].
CANCER
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
NORMAL
CELL
Oxidative stress,
Carcinogens,
Viruses
Modulation
of Cell Fate
DNA
Damage/Epigenetic
Alterations
Cell cycle arrest
DNA repair
Successful
DNA Repair
APOPTOSIS
Cyclin E
CDK2
P27
Kip 1
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
CDK
2/4/6
Cyclin
D/E/A
Vit. D
Degradation
RXR
M
G1
S
G2
P27
Kip 1
SKP2 P27
Kip 1
VDR
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 [83]. 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 [84].
Experimental studies have depicted that
1,25(OH)2D3 suppresses human colonic cell and colon
cancer cell line proliferation [85]. 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) [49]. For the functional
activations of CDKs, their association with functional
subunits (cyclins) is required [86]. 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 [87]. 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 [88]. 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 [89].
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 [90]. 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
[91]. 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 [92].
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 [93]. 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” [94].
6.1. Carotenoids
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 [95]. Meta-analysis demonstrated
that high vitamin A intake was linked with a reduced
risk of bladder cancer [2].
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 [96]. 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 [97]. 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 [98]. 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 [99]. β-
carotene was also related with an elevated risk of
aggressive PC [100]. 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 [100].
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 [101].
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,
0.470.97) and lutein (OR = 0.55; 95% CI, 0.370.81)
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 [102]. 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
[103].
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 [104]. 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 [61]. 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
[105]. 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 [106]. 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 [81]. 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 [107]. A lowered risk was
found in vitamin E intake when studies were conducted
in a three casecontrol 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 [100]. 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 [108]. 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
[109]. 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 [110].
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 [113]. 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 [114]. 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 [115]. 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 [116]. It suggested that antifolates, paired
with existing strategies, may remarkably enhance the
treatment of prostate cancer [116]. 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 [117]. 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 [120]. 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
[121]. 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 [115].
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 [122]. 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 [123].
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 [124]. 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 [94]. 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 [125].
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 [126].
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
[127]. 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 [61]. 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 [128]. 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 [129].
7. PHARMACEUTICAL ROLE OF VITAMINS IN
CANCER THERAPY
Commercial varieties of vitamin formulations are
available to treat the deficiency. Cancer, life
threatening disease causes serious illness worldwide
[130]. 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) [136].
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
20300 nm for the effectively extravasate in leaky
vesicles [138]. 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 [139]. 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 [133]. 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) [140]. 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) [147].
336 Current Molecular Medicine, 2017, Vol. 17, No. 5 Jain et al.
Table 4. Vitamin E-based nanomedicines for anticancer drug delivery.
Based Carrier
Type
Composition
Drug
Model for the Study
Studies
Refs.
Tocopherol
Polymeric
nanoparticles
mPEG-PLA-tocopherol
DOX
Breast and uterine cancer
In vitro and in vivo
[148]
Oligomersomes
α-Tocopherol
oligochitosan
SiRNA
Human epidermal
carcinoma
In vitro and in vivo
[149]
Micelles
Chitosan/TOS copolymer
PTX
Cervical cancer
In vitro and in vivo
[150-
152]
TOS modified pluronic
PTX
Glioma
In vitro and in vivo
[153]
TPGS
Mixed micelles
Pluronic P407/TPGS
Gambogic acid
Breast and MDR cancer
In vitro
[154]
Pluronic P123/TPGS
Quercetin
Breast cancer
In vitro
[155]
Pluronic P105/TPGS
CPT
Breast cancer
In vitro
[156]
DSPE-PEG/TPGS
PTX and
parthenolide
NSCLC
In vitro
[157]
Micelles
PLV(2K)
DOX
Breast and MDR cancer
In vitro and in vivo
[158]
FOL-TPGS2000
DOC
Breast cancer
In vitro
[159]
Liposomes
TPGS coating
DOC and QDs
Breast cancer
In vitro
[160]
DOC
Glioma
In vitro
[161]
Emodin
B-cell lymphoma
In vitro and in vivo
[162]
Topotecan
Breast and melanoma
metastatic cancer
In vitro and in vivo
[135,
163]
Trastuzumab-conjugated
TPGS
DOC
Breast cancer
In vitro and in vivo
[164,
165]
Complex
nanoparticles
Pluronic P85-PEI/TPGS
PTX and shRNA
Lung and breast cancer
In vitro and in vivo
[166,
167]
Nanocrystals
TPGS
PTX
NSCLC
In vitro and in vivo
[168]
Polymeric
nanoparticles
TPGS + 4-armed
porphyrin-PLA
DOX
Breast cancer
In vitro
[169]
TPGS + MPEG-SS-PLA
PTX
Lung, breast and uterus
cancer
In vitro
[170]
FOLTPGS and DOX
PLGATPGS
DOX
Breast cancer
In vitro
[171]
PLATPGS +
trastuzumabTPGS
DOC
Breast cancer
In vitro
[172]
Prodrug
TPGSDOX
DOX
Breast cancer
In vitro and in vivo
[173]
TPGSDOXFOL
DOX
Breast cancer
In vitro and in vivo
[173]
TPGScisplatin
Cisplatin
Hepatocarcinoma
In vitro
[174]
Hepatocarcinoma In vitro
Cisplatin, DOC and
herceptin
Breast cancer
In vitro
[175]
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
Resistance
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
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial
or otherwise.
ACKNOWLEDGEMENTS
Declared none.
REFERENCES
[1] Masri OA, Chalhoub JM, Sharara AI. Role of vitamins in
gastrointestinal diseases. World J Gastroenterol 2015;
21(17): 5191-209.
[2] Tang JE, Wang RJ, Zhong H, Yu B, Chen Y. Vitamin A and
risk of bladder cancer: a meta-analysis of epidemiological
studies. World J Surg Oncol 2014; 12: 130.
[3] Funk C. The etiology of the deficiency diseases. Journal of
State Medicine 1912; 20(6): 341-68.
[4] Dolara P, Bigagli E, Collins A. Antioxidant vitamins and
mineral supplementation, life span expansion and cancer
incidence: a critical commentary. Eur J Nutr 2012; 51(7): 769-
81.
[5] Hopkins FG. Feeding experiments illustrating the importance
of accessory factors in normal dietaries. J Physiol 1912; 44(5-
6): 425-60.
[6] Shigemura Y, Takeshita K, Kitayama K, Tanaka H, Koshii Y.
[Evaluation of learning and education of nursing personnel:
application of pre- and post-training tests for the improvement
of learning activities]. Nasu Suteshon 1986; 16(3): 273-7.
[7] Harris PL. Fat soluble vitamins. Annu Rev Biochem 1949;
18(1): 391-434.
[8] Dowling JE, Wald G. The biological function of vitamin A acid.
Proc Natl Acad Sci U S A 1960; 46(5): 587-608.
[9] Sommer A. Vitamin A deficiency: Wiley Online Library; 2001.
[10] Penniston KL, Tanumihardjo SA. The acute and chronic toxic
effects of vitamin A. Am J Clin Nutr 2006; 83(2): 191-201.
[11] DeLuca HF. Overview of general physiologic features and
functions of vitamin D. Am J Clin Nutr 2004; 80(6): 1689S-
96S.
[12] Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357(3):
266-81.
[13] Vieth R. Toxicity of vitamin D. Vitamin D: Springer; 2010. p.
603-12.
[14] Fuchs J, Packer L. Vitamin E in health and disease: 1992; pp.
1000.
[15] Dowd P, Zheng ZB. On the mechanism of the anticlotting
action of vitamin E quinone. Proc Natl Acad Sci U S A 1995;
92(18): 8171-5.
[16] Burton GW. Vitamin E: molecular and biological function.
Proc Nutr Soc 1994; 53(02): 251-62.
[17] Bieri JG, Corash L, Hubbard VS. Medical uses of vitamin E. N
Engl J Med 1983; 308(18): 1063-71.
[18] Chen TC, Chimeh F, Lu Z, et al. Factors that influence the
cutaneous synthesis and dietary sources of vitamin D. Arch
Biochem Bioph 2007; 460(2): 213-7.
[19] Shils ME, Shike M. Modern nutrition in health and disease:
Lippincott Williams & Wilkins; 2006.
[20] Friedman PA. Vitamin K-Dependent Proteins. Mass Medical
Soc; 1984.
[21] Williams RR, Spies TD. Vitamin B1 and its use in medicine.
The Macmillan Company; 1938.
[22] Rivlin RS, Pinto JT. Riboflavin (vitamin B2). Handbook of
vitamins, 3rd ed. New York: Marcel Dekker. 2001: 255-73.
[23] Chi Y, Sauve AA. Nicotinamide riboside, a trace nutrient in
foods, is a vitamin B3 with effects on energy metabolism and
neuroprotection. Curr Opin Clin Nutr Metab Care 2013; 16(6):
657-61.
[24] Eddy WH, Gurin S, Keresztesy J. The Williams-Waterman
Vitamin B3. J Biol Chem 1930; 87(3): 729-40.
[25] McDowell LR. Vitamins in animal nutrition: comparative
aspects to human nutrition: Elsevier; 2012.
[26] Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6
from diet and supplements in relation to risk of coronary heart
disease among women. JAMA 1998; 279(5): 359-64.
[27] Bender D. Vitamin B6 requirements and recommendations.
Eur J Clin Nutr 1989; 43(5): 289-309.
[28] Polyak S, Bailey L, Azhar A, Booker G. Biotin (Vitamin H or
B7). Micronutrients: Sources, properties and health benefits
Nova Science Publishers, New York, USA. 2012.
[29] Guilland J-C, Aimone-Gastin I. Vitamin B9. Rev Prat 2013;
63(8): 1079, 81-4.
[30] Smith EL. Vitamin B12. Vitamin B12, 3rd ed. Methuen & Co.
Ltd., London; John Wiley & Sons Inc., New York. 1965.
[31] Herbert V. Staging vitamin B-12 (cobalamin) status in
vegetarians. Am J Clin Nutr 1994; 59(5): 1213S-22S.
[32] Stabler SP. Vitamin B12 deficiency. N Engl J Med 2013;
368(2): 149-60.
[33] Linster CL, Van Schaftingen E. Vitamin C. FEBS J 2007;
274(1): 1-22.
[34] Bendich A, Machlin L, Scandurra O, Burton G, Wayner D.
The antioxidant role of vitamin C. Free Radic Biol Med 1986;
2(2): 419-44.
[35] Rusznyak S, Szent-Györgyi A. Vitamin P: flavonols as
vitamins. Nature 1936; 138: 27.
[36] Hooper L, Kroon PA, Rimm EB, et al. Flavonoids, flavonoid-
rich foods, and cardiovascular risk: a meta-analysis of
randomized controlled trials. Am J Clin Nutr 2008; 88(1): 38-
50.
[37] Young VR, Newberne PM. Vitamins and cancer prevention:
issues and dilemmas. Cancer 1981; 47(S5): 1226-40.
[38] Lee KW, Lee HJ, Surh YJ, Lee CY. Vitamin C and cancer
chemoprevention: reappraisal. Am J Clin Nutr 2003; 78(6):
1074-8.
[39] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA
Cancer J Clin 2016; 66(1): 7-30.
[40] Higginson J, Muir CS. Environmental carcinogenesis:
misconceptions and limitations to cancer control. J Natl
Cancer Inst 1979; 63(6): 1291-8.
[41] Crew KD, Neugut AI. Epidemiology of gastric cancer. World J
Gastroenterol 2006; 12(3): 354.
[42] Yang M, Oh HK, Shim YM, Shin MH. Differential prognostic
effect of smoking and multivitamin use on lung cancer
survival by sex. Cancer Res 2016; 76(14 Suppl): 3418-8.
[43] Meyskens J, Prasad KN. Vitamins and Cancer: Human
Cancer Prevention by Vitamins and Micronutrients: Springer
Science & Business Media; 2012.
[44] Fortmann SP, Burda BU, Senger CA, Lin JS, Whitlock EP.
Vitamin and mineral supplements in the primary prevention of
cardiovascular disease and cancer: an updated systematic
evidence review for the US Preventive Services Task Force.
Ann Intern Med 2013; 159(12): 824-34.
[45] Hardy ML, Duvall K. Multivitamin/multimineral supplements
for cancer prevention: implications for primary care practice.
Postgrad Med 2015; 127(1): 107-16.
[46] Spom MB, Roberts AB. Role of retinoids in differentiation and
carcinogenesis. Cancer Res 1983; 43(7): 3034-40.
[47] DiGiovanni J. Inhibition of chemical carcinogenesis. Chemical
Carcinogenesis and Mutagenesis II: Springer; 1990. p. 159-
223.
[48] van Poppel G, van den Berg H. Vitamins and cancer. Cancer
Lett 1997; 114(1): 195-202.
[49] Lupulescu AP. Hormones, vitamins, and growth factors in
cancer treatment and prevention: A critical appraisal. Cancer
1996; 78(11): 2264-80.
338 Current Molecular Medicine, 2017, Vol. 17, No. 5 Jain et al.
[50] De Vet H. The puzzling role of vitamin A in cancer prevention
(review). Anticancer Res 1988; 9(1): 145-51.
[51] Bendich A. Carotenoids and the immune response. J Nutr.
1989; 119(1): 112-5.
[52] Mamede AC, Tavares SD, Abrantes AM, Trindade J, Maia
JM, Botelho MF. The role of vitamins in cancer: a review. Nutr
Cancer. 2011; 63(4): 479-94.
[53] Hanck AB. Vitamin C and cancer. Prog. Clin. Biol. Res. 1988;
259: 307-20.
[54] Schwartz J, Shklar G, Trickler D. Vitamin C enhances the
development of carcinomas in the hamster buccal pouch
experimental model. Oral Surg. Oral Med. Oral Pathol. 1993
Dec; 76(6): 718-22.
[55] Cameron E, Pauling L. Supplemental ascorbate in the
supportive treatment of cancer: Prolongation of survival times
in terminal human cancer. Proc. Natl. Acad. Sci. U.S.A. 1976
Oct; 73(10): 3685-9.
[56] Krishnan AV, Feldman D. Mechanisms of the anti-cancer and
anti-inflammatory actions of vitamin D. Annu Rev Pharmacol
Toxicol. 2011; 51: 311-36.
[57] Vijayakumar S. Prevention of Post-Radiotherapy Failure in
Prostate Cancer by Vitamin D. DTIC Document, 2003.
[58] Colston KW, Mackay AG, James SY, Binderup L, Chander S,
Coombes RC. EB1089: a new vitamin D analogue that
inhibits the growth of breast cancer cells in vivo and in vitro.
Biochem Pharmacol. 1992; 44(12): 2273-80.
[59] Knekt P. Vitamin E and cancer: epidemiology. Ann N Y Acad
Sci. 1992; 669(1): 269-79.
[60] Lupulescu A. The role of vitamins A, beta-carotene, E and C
in cancer cell biology. Int J Vitam Nutr Res. 1993; 64(1): 3-14.
[61] Vance TM, Su J, Fontham ET, Koo SI, Chun OK. Dietary
antioxidants and prostate cancer: a review. Nutr Cancer.
2013; 65(6): 793-801.
[62] Lupulescu A. Hormones and vitamins in cancer treatment:
CRC Press; 1990.
[63] Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson
IM, Ford LG, et al. Effect of selenium and vitamin E on risk of
prostate cancer and other cancers: the Selenium and Vitamin
E Cancer Prevention Trial (SELECT). Jama. 2009; 301(1):
39-51.
[64] Kawa S, Nikaido T, Aoki Y, et al. Vitamin D analogs up-
regulate p21 and p27 during growth inhibition of pancreatic
cancer cell lines. Br J Cancer. 1997; 76(7): 884.
[65] Garland CF, Garland FC, Gorham ED, et al. The role of
vitamin D in cancer prevention. American journal of public
health. 2006; 96(2): 252-61.
[66] Huynh H, Pollak M, Zhang JC. Regulation of insulin-like
growth factor (IGF) II and IGF binding protein 3 autocrine loop
in human PC-3 prostate cancer cells by vitamin D metabolite
1, 25 (OH) 2D3 and its analog EB1089. Int J Oncol. 1998;
13(1): 137-44.
[67] Skowronski RJ, Peehl DM, Feldman D. Vitamin D and
prostate cancer: 1, 25 dihydroxyvitamin D3 receptors and
actions in human prostate cancer cell lines. Endocrinology.
1993; 132(5): 1952-60.
[68] Wagner D, Trudel D, Van der Kwast T, et al. Randomized
clinical trial of vitamin D3 doses on prostatic vitamin D
metabolite levels and ki67 labeling in prostate cancer
patients. J Clin Endocrinol Metab. 2013; 98(4): 1498-507.
[69] Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a
combination of beta carotene and vitamin A on lung cancer
and cardiovascular disease. N Engl J Med. 1996; 334(18):
1150-5.
[70] Singh VN, Gaby SK. Premalignant lesions: role of antioxidant
vitamins and beta-carotene in risk reduction and prevention
of malignant transformation. Am J Clin Nutr. 1991; 53(1):
386S-90S.
[71] Meyerhardt JA, Niedzwiecki D, Hollis D, et al. Association of
dietary patterns with cancer recurrence and survival in
patients with stage III colon cancer. Jama. 2007; 298(7): 754-
64.
[72] Ng K, Meyerhardt JA, Wu K, et al. Circulating 25-
hydroxyvitamin d levels and survival in patients with
colorectal cancer. J Clin Oncol. 2008; 26(18): 2984-91.
[73] Ingraham BA, Bragdon B, Nohe A. Molecular basis of the
potential of vitamin D to prevent cancer. Curr Med Res Opin.
2008; 24(1): 139-49.
[74] DeLuca H, Omdahl J, Holick M, Suda T, Tanaka Y. Biological
activity 1, 25-dihydroxycholecalciferol. Biochemistry. 1971;
10(15): 2935-40.
[75] Awada A, Di Leo A, Piccart-Gebhart M. New Biological
approaches to the treatment of cancer with a focus on breast
cancer. Bull Cancer. 2000; 87(1): 49-62.
[76] Dai X, Yamasaki K, Yang L, et al. Keratinocyte G2/M growth
arrest by 1, 25-dihydroxyvitamin D3 is caused by Cdc2
phosphorylation through Wee1 and Myt1 regulation. J Invest
Dermatol. 2004; 122(6): 1356-64.
[77] Han SH, Jeon JH, Ju HR, et al. VDUP1 upregulated by TGF-
β1 and 1, 25-dihydorxyvitamin D3 inhibits tumor cell growth
by blocking cell-cycle progression. Oncogene. 2003; 22(26):
4035-46.
[78] Liu M, Lee M-H, Cohen M, Bommakanti M, Freedman LP.
Transcriptional activation of the Cdk inhibitor p21 by vitamin
D3 leads to the induced differentiation of the myelomonocytic
cell line U937. Genes Dev. 1996; 10(2): 142-53.
[79] Antonsson B, Martinou JC. The Bcl-2 protein family. Exp Cell
Res. 2000; 256(1): 50-7.
[80] Ylikomi T, Laaksi I, Lou YR, et al. Antiproliferative action of
vitamin D. Vitam Horm. 2002; 64: 357-406.
[81] Jiang F, Bao J, Li P, Nicosia SV, Bai W. Induction of ovarian
cancer cell apoptosis by 1, 25-dihydroxyvitamin D3 through
the down-regulation of telomerase. J Biol Chem. 2004;
279(51): 53213-21.
[82] Jiang F, Li P, Fornace AJ, Nicosia SV, Bai W. G2/M arrest by
1, 25-dihydroxyvitamin D3 in ovarian cancer cells mediated
through the induction of GADD45 via an exonic enhancer. J
Biol Chem. 2003; 278(48): 48030-40.
[83] Townsend K, Banwell CM, Guy M, Colston KW, Mansi JL,
Stewart PM, et al. Autocrine metabolism of vitamin D in
normal and malignant breast tissue. Clin Cancer Res. 2005;
11(9): 3579-86.
[84] vinh quoc Luong K, Nguyen LTH. The beneficial role of
vitamin D and its analogs in cancer treatment and prevention.
Crit Rev Oncol Hematol. 2010; 73(3): 192-201.
[85] Shabahang M, Buras RR, Davoodi F, et al. Growth inhibition
of HT-29 human colon cancer cells by analogs of 1, 25-
dihydroxyvitamin D3. Cancer Res. 1994; 54(15): 4057-64.
[86] Pines J. Cyclins and cyclin-dependent kinases: a biochemical
view. Biochem J. 1995; 308(Pt 3): 697.
[87] Wang QM, Jones JB, Studzinski GP. Cyclin-dependent
kinase inhibitor p27 as a mediator of the G1-S phase block
induced by 1, 25-dihydroxyvitamin D3 in HL60 cells. Cancer
Res. 1996; 56(2): 264-7.
[88] Munker R, Kobayashi T, Elstner E, et al. A new series of
vitamin D analogs is highly active for clonal inhibition,
differentiation, and induction of WAF1 in myeloid leukemia.
Blood. 1996; 88(6): 2201-9.
[89] Liu W, Asa SL, Fantus IG, Walfish PG, Ezzat S. Vitamin D
arrests thyroid carcinoma cell growth and induces p27
dephosphorylation and accumulation through PTEN/akt-
dependent and-independent pathways. Am J Pathol. 2002;
160(2): 511-9.
[90] Kohl NE, Conner MW, Gibbs JB, Graham SL, Hartman GD,
Oliff A. Development of inhibitors of protein farnesylation as
potential chemotherapeutic agents. J Cell Biochem. 1995;
59(S22): 145-50.
[91] Irani K, Xia Y, Zweier JL, et al. Mitogenic signaling mediated
by oxidants in Ras-transformed fibroblasts. Science. 1997;
275(5306): 1649-52.
[92] Banerjee P, Chatterjee M. Antiproliferative role of vitamin D
and its analogsa brief overview. Mol Cell Biochem. 2003;
253(1-2): 247-54.
[93] Smith!Warner SA, Spiegelman D, Yaun SS, et al. Fruits,
vegetables and lung cancer: a pooled analysis of cohort
studies. Int J Cancer. 2003; 107(6): 1001-11.
[94] Li Y, Wicha MS, Schwartz SJ, Sun D. Implications of cancer
stem cell theory for cancer chemoprevention by natural
dietary compounds. J Nutr Biochem. 2011 Sep; 22(9): 799-
806.
Vitamins for Cancer Prevention and Treatment: An Insight Current Molecular Medicine, 2017, Vol. 17, No. 5 339
[95] Brunner R, Dunbar-Jacob J, LeBoff MS, et al. Predictors of
adherence in the women's health initiative calcium and
vitamin D trial. Behav Med. 2009; 34(4): 145-55.
[96] Goodman GE, Thornquist MD, Balmes J, et al. The Beta-
Carotene and Retinol Efficacy Trial: incidence of lung cancer
and cardiovascular disease mortality during 6-year follow-up
after stopping β-carotene and retinol supplements. J Natl
Cancer Inst. 2004; 96(23): 1743-50.
[97] Ziegler RG. A review of epidemiologic evidence that
carotenoids reduce the risk of cancer. J Nutr. 1989; 119(1):
116-22.
[98] Männistö S, Smith-Warner SA, Spiegelman D, et al. Dietary
carotenoids and risk of lung cancer in a pooled analysis of
seven cohort studies. Cancer Epidemiol Biomarkers Prev.
2004; 13(1): 40-8.
[99] Heinonen OP, Koss L, Albanes D, et al. Prostate cancer and
supplementation with α-tocopherol and β-carotene: incidence
and mortality in a controlled trial. J Natl Cancer Inst. 1998;
90(6): 440-6.
[100] Ma RL, Chapman K. A systematic review of the effect of diet
in prostate cancer prevention and treatment. J Hum Nutr Diet.
2009; 22(3): 187-99.
[101] Virtamo J, Pietinen P, Huttunen J, Korhonen P, Malila N,
Virtanen M, et al. Incidence of cancer and mortality following
alpha-tocopherol and beta-carotene supplementation: a
postintervention follow-up. Jama. 2003; 290(4): 476-85.
[102] McCann SE, Ambrosone CB, Moysich KB, et al. Intakes of
selected nutrients, foods, and phytochemicals and prostate
cancer risk in western New York. Nutr Cancer. 2005; 53(1):
33-41.
[103] Schuurman A, Van den Brandt P, Dorant E, Goldbohm R.
Animal products, calcium and protein and prostate cancer risk
in The Netherlands Cohort Study. Br J Cancer. 1999; 80(7):
1107.
[104] Ju J, Picinich SC, Yang Z, et al. Cancer-preventive activities
of tocopherols and tocotrienols. Carcinogenesis. 2009; 31(4):
533-42.
[105] Gupta SD, Sae-Tan S, Wahler J, et al. Dietary γ-Tocopherol
Rich Mixture Inhibits Estrogen-Induced Mammary
Tumorigenesis by Modulating Estrogen Metabolism,
Antioxidant Response, and PPARγ. Cancer Prev Res. 2015;
8(9): 807-16.
[106] Ju J, Lee GY, Kim YS, Chang HK, Do MS, Park KY. Bamboo
Salt Suppresses Colon Carcinogenesis in C57BL/6 Mice with
Chemically Induced Colitis. J Med Food. 2016; 19(11): 1015-
22.
[107] Santillo VM, Lowe FC. Role of vitamins, minerals and
supplements in the prevention and management of prostate
cancer. Int Braz J Urol. 2006; 32(1): 3-14.
[108] Knowles S, Wilson S, Huang Q, Fink A. C4-4: Prevalence of
Hazardous and Harmful Drinking Patterns Among Older US
Adults: Data from the 20052008 NHANES. Clin Med Res.
2013; 11(3): 170-1.
[109] Heinonen OP, Albanes D. The effect of vitamin E and beta
carotene on the incidence of lung cancer and other cancers
in male smokers. N Engl J Med. 1994; 330(15): 1029-35
[110] Schmid HP, Fischer C, Engeler DS, Bendhack ML, Schmitz-
Drager BJ. Nutritional aspects of primary prostate cancer
prevention. Recent Results Cancer Res. 2011; 188: 101-7.
[111] Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ.
Folate intake and colorectal cancer risk: a meta!analytical
approach. Int J Cancer. 2005; 113(5): 825-8.
[112] Jäger E, Klein O, Wächter B, Müller B, Braun U, Knuth A.
Second-line treatment with high-dose 5-fluorouracil and folinic
acid in advanced colorectal cancer refractory to standard-
dose 5-fluorouracil treatment. Oncology. 1995; 52(6): 470-3.
[113] Kennedy DA, Stern SJ, Moretti M, et al. Folate intake and the
risk of colorectal cancer: a systematic review and meta-
analysis. Cancer Epidemiol. 2011; 35(1): 2-10.
[114] Figueiredo JC, Mott LA, Giovannucci E, Wu K, Cole B,
Grainge MJ, et al. Folic acid and prevention of colorectal
adenomas: a combined analysis of randomized clinical trials.
Int J Cancer. 2011; 129(1): 192-203.
[115] Martínez ME, Jacobs ET, Baron JA, Marshall JR, Byers T.
Dietary supplements and cancer prevention: balancing
potential benefits against proven harms. J Natl Cancer Inst.
2012; 104(10): 732-9.
[116] Bistulfi G, Foster BA, Karasik E, et al. Dietary folate
deficiency blocks prostate cancer progression in the TRAMP
model. Cancer Prev Res. 2011; 4(11): 1825-34.
[117] Roswall N, Olsen A, Christensen J, Dragsted LO, Overvad K,
Tjonneland A. Micronutrient intake and risk of colon and
rectal cancer in a Danish cohort. Cancer Epidemiol. 2010
Feb; 34(1): 40-6.
[118] Schernhammer ES, Giovannuccci E, Fuchs CS, Ogino S. A
prospective study of dietary folate and vitamin B and colon
cancer according to microsatellite instability and KRAS
mutational status. Cancer Epidemiol Biomarkers Prev. 2008
Oct; 17(10): 2895-8.
[119] Schernhammer ES, Ogino S, Fuchs CS. Folate and vitamin
B6 intake and risk of colon cancer in relation to p53
expression. Gastroenterology. 2008 Sep; 135(3): 770-80.
[120] Chen P, Hu P, Xie D, Qin Y, Wang F, Wang H. Meta-analysis
of vitamin D, calcium and the prevention of breast cancer.
Breast Cancer Res Treat. 2010 Jun; 121(2): 469-77.
[121] Van Poppel H, Tombal B. Chemoprevention of prostate
cancer with nutrients and supplements. Cancer Manag Res.
2011; 3: 91.
[122] Pommergaard HC, Burcharth J, Rosenberg J, Raskov H.
Chemoprevention with acetylsalicylic acid, vitamin D and
calcium reduces risk of carcinogen-induced lung tumors.
Anticancer Res. 2013 Nov; 33(11): 4767-70.
[123] Hosono S, Matsuo K, Kajiyama H, et al. Association between
dietary calcium and vitamin D intake and cervical
carcinogenesis among Japanese women. Eur J Clin Nutr.
2010 Apr; 64(4): 400-9.
[124] Pálmer HG, González-Sancho JM, Espada J, et al. Vitamin
D3 promotes the differentiation of colon carcinoma cells by
the induction of E-cadherin and the inhibition of β-catenin
signaling. J Cell Biol. 2001; 154(2): 369-88.
[125] Hummel DM, Thiem U, Hobaus J, et al. Prevention of
preneoplastic lesions by dietary vitamin D in a mouse model
of colorectal carcinogenesis. J Steroid Biochem Mol Biol.
2013 Jul; 136: 284-8.
[126] de Munter L, Maasland DH, van den Brandt PA, Kremer B,
Schouten LJ. Vitamin and carotenoid intake and risk of head-
neck cancer subtypes in the Netherlands Cohort Study. Am J
Clin Nutr. 2015 Aug; 102(2): 420-32.
[127] Zhou S, Wang X, Tan Y, Qiu L, Fang H, Li W. Association
between vitamin C intake and glioma risk: evidence from a
meta-analysis. Neuroepidemiology. 2015; 44(1): 39-44.
[128] Durak Y, Kokcu A, Kefeli M, Bildircin D, Celik H, Alper T.
Effect of vitamin C on the growth of experimentally induced
endometriotic cysts. J Obstet Gynaecol Res. 2013 Jul; 39(7):
1253-8.
[129] Cha J, Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A,
Rath M. Ascorbate supplementation inhibits growth and
metastasis of B16FO melanoma and 4T1 breast cancer cells
in vitamin C-deficient mice. Int J Oncol. 2013 Jan; 42(1): 55-
64.
[130] Danhier F, Feron O, Preat V. To exploit the tumor
microenvironment: Passive and active tumor targeting of
nanocarriers for anti-cancer drug delivery. J Control Release.
2010 Dec 1; 148(2): 135-46.
[131] Jain A, Gulbake A, Jain A, Shilpi S, Hurkat P, Jain SK. Dual
drug delivery using “smart” liposomes for triggered release of
anticancer agents. J Nanopart Res. 2013; 15(7): 1-12.
[132] Kumari A, Jain A, Hurkat P, Verma A, Jain SK.
Microsponges: A Pioneering Tool for Biomedical Applications.
Crit Rev Ther Drug Carrier Syst. 2016; 33(1): 77-105.
[133] Jain A, Jain SK. Ligand-mediated drug-targeted liposomes.
UK: Future Medicine 2016; 144-58.
[134] Jain A, Jain SK. Multipronged, strategic delivery of paclitaxel-
topotecan using engineered liposomes to ovarian cancer.
Drug Dev Ind Pharm. 2015 Jun 2: 1-14.
[135] Jain A, Jain SK. Chapter 9: Application Potential of
Engineered Liposomes in Tumor Targeting. Multifunctional
Systems for Combined Delivery, Biosensing and Diagnostics:
Elsevier - Health Sciences Division, https:
//www.elsevier.com/books/multifunctional-systems-for-
340 Current Molecular Medicine, 2017, Vol. 17, No. 5 Jain et al.
combined-delivery-biosensing-and-
diagnostics/grumezescu/978-0-323-52725-5; 2017. p. 171-
92.
[136] Jain RK, Stylianopoulos T. Delivering nanomedicine to solid
tumors. Nature Rev Clin Oncol. 2010; 7(11): 653-64.
[137] Steichen SD, Caldorera-Moore M, Peppas NA. A review of
current nanoparticle and targeting moieties for the delivery of
cancer therapeutics. Eur J Pharm Sci. 2013; 48(3): 416-27.
[138] Jain A, Jain SK. Stimuli-Responsive Smart Liposomes in
Cancer Targeting. Curr Drug Targets. 2016; 17(11): 1-12.
[139] Saraf S, Jain A, Hurkat P, Jain S. Topotecan liposomes
(TLs): A visit from molecular to therapeutic platform. Crit Rev
Ther Drug Carrier Syst. 2016; 33(5): 40132.
[140] Dangi R, Hurkat P, Jain A, et al. Targeting liver cancer via
ASGP receptor using 5-FU-loaded surface-modified PLGA
nanoparticles. J Microencapsul. 2014; 31(5): 479-87.
[141] Jain A, Jain SK. Ligand-Appended BBB-Targeted
Nanocarriers (LABTNs). Crit Rev Ther Drug Carrier Syst.
2015 2015-04-22; 32(2): 149-80.
[142] Jain A, Jain SK. Colon Targeted Liposomal Systems (CTLS):
Theranostic Potential. Curr Mol Med. 2015; 15(7): 621-33.
[143] Zhang Z, Tan S, Feng S-S. Vitamin E TPGS as a molecular
biomaterial for drug delivery. Biomaterials. 2012; 33(19):
4889-906.
[144] Wong RS, Radhakrishnan AK. Tocotrienol research: past into
present. Nutr Rev. 2012; 70(9): 483-90.
[145] Kline K, Lawson KA, Yu W, Sanders BG. Vitamin E and
cancer. Vitam Horm. 2007; 76: 435-61.
[146] Constantinou C, Papas A, Constantinou AI. Vitamin E and
cancer: an insight into the anticancer activities of vitamin E
isomers and analogs. Int J Cancer. 2008; 123(4): 739-52.
[147] Duhem N, Danhier F, Préat V. Vitamin E-based
nanomedicines for anti-cancer drug delivery. J Control
Release. 2014; 182: 33-44.
[148] Yi Y, Kim JH, Kang H-W, Oh HS, Kim SW, Seo MH. A
polymeric nanoparticle consisting of mPEG-PLA-Toco and
PLMA-COONa as a drug carrier: improvements in cellular
uptake and biodistribution. Pharm Res. 2005; 22(2): 200-8.
[149] Noh SM, Han SE, Shim G, et al. Tocopheryl oligochitosan-
based self assembling oligomersomes for siRNA delivery.
Biomaterials. 2011; 32(3): 849-57.
[150] Liang N, Sun S, Li X, et al. α-Tocopherol succinate-modified
chitosan as a micellar delivery system for paclitaxel:
preparation, characterization and in vitro/in vivo evaluations.
Int J Pharm. 2012; 423(2): 480-8.
[151] Jain A, Gulbake A, Shilpi S, Jain A, Hurkat P, Jain SK. A new
horizon in modifications of chitosan: syntheses and appli-
cations. Crit Rev Ther Drug Carrier Syst. 2013; 30(2): 91-181.
[152] Jain A, Jain SK. Engineered chitosan: A potential tool in
biomedical applications. Int J Biotechnol Bioeng Res. 2013;
4(3): 1-4.
[153] Tao Y, Han J, Wang X, Dou H. Nano-formulation of paclitaxel
by vitamin E succinate functionalized pluronic micelles for
enhanced encapsulation, stability and cytotoxicity. Colloids
Surf B Biointerfaces. 2013; 102: 604-10.
[154] Saxena V, Hussain MD. Poloxamer 407/TPGS mixed
micelles for delivery of gambogic acid to breast and
multidrug-resistant cancer. Int J Nanomed. 2012; 7: 713-21.
[155] Zhao L, Shi Y, Zou S, Sun M, Li L, Zhai G. Formulation and in
vitro evaluation of quercetin loaded polymeric micelles
composed of pluronic P123 and Da-tocopheryl polyethylene
glycol succinate. J Biomed Nanotechnol. 2011; 7(3): 358-65.
[156] Gao Y, Li LB, Zhai G. Preparation and characterization of
Pluronic/TPGS mixed micelles for solubilization of
camptothecin. Colloids Surf B Biointerfaces. 2008; 64(2):
194-9.
[157] Gill KK, Kaddoumi A, Nazzal S. Mixed micelles of PEG 2000-
DSPE and vitamin-E TPGS for concurrent delivery of
paclitaxel and parthenolide: Enhanced chemosenstization
and antitumor efficacy against non-small cell lung cancer
(NSCLC) cell lines. Eur J Pharm Sci. 2012; 46(1): 64-71.
[158] Wang J, Sun J, Chen Q, et al. Star-shape copolymer of
lysine-linked di-tocopherol polyethylene glycol 2000 succinate
for doxorubicin delivery with reversal of multidrug resistance.
Biomaterials. 2012; 33(28): 6877-88.
[159] Mi Y, Liu Y, Feng SS. Formulation of docetaxel by folic acid-
conjugated d-α-tocopheryl polyethylene glycol succinate 2000
(Vitamin E TPGS 2k) micelles for targeted and synergistic
chemotherapy. Biomaterials. 2011; 32(16): 4058-66.
[160] Muthu MS, Kulkarni SA, Raju A, Feng SS. Theranostic
liposomes of TPGS coating for targeted co-delivery of
docetaxel and quantum dots. Biomaterials. 2012 Apr; 33(12):
3494-501.
[161] Muthu MS, Kulkarni SA, Xiong J, Feng SS. Vitamin E TPGS
coated liposomes enhanced cellular uptake and cytotoxicity
of docetaxel in brain cancer cells. Int J Pharm. 2011 Dec 15;
421(2): 332-40.
[162] Wang T, Yin X, Lu Y, Shan W, Xiong S. Formulation,
antileukemia mechanism, pharmacokinetics, and
biodistribution of a novel liposomal emodin. Int J Nanomed.
2012; 7: 2325-37.
[163] Yu Y, Wang ZH, Zhang L, et al. Mitochondrial targeting
topotecan-loaded liposomes for treating drug-resistant breast
cancer and inhibiting invasive metastases of melanoma.
Biomaterials. 2012 Feb; 33(6): 1808-20.
[164] Raju A, Muthu MS, Feng SS. Trastuzumab-conjugated
vitamin E TPGS liposomes for sustained and targeted
delivery of docetaxel. Expert Opin Drug Del. 2013 Jun; 10(6):
747-60.
[165] Jain A, Jain SK. Liposomes in Cancer Therapy. Nanocarrier
Systems for Drug Delivery: Nova Science Publishers, https:
//www.novapublishers.com/catalog/product_info.php?product
s_id=59761&osCsid=e7d370318f328e75748328a1e44e48aa;
2016. p. 1-42.
[166] Shen J, Yin Q, Chen L, Zhang Z, Li Y. Co-delivery of
paclitaxel and survivin shRNA by pluronic P85-PEI/TPGS
complex nanoparticles to overcome drug resistance in lung
cancer. Biomaterials. 2012; 33(33): 8613-24.
[167] Shen J, Sun H, Xu P, et al. Simultaneous inhibition of
metastasis and growth of breast cancer by co-delivery of twist
shRNA and paclitaxel using pluronic P85-PEI/TPGS complex
nanoparticles. Biomaterials. 2013; 34(5): 1581-90.
[168] Liu Y, Huang L, Liu F. Paclitaxel nanocrystals for overcoming
multidrug resistance in cancer. Mol Pharm. 2010; 7(3): 863-9.
[169] Shieh MJ, Hsu CY, Huang LY, Chen HY, Huang FH, Lai PS.
Reversal of doxorubicin-resistance by multifunctional
nanoparticles in MCF-7/ADR cells. J Control Release. 2011;
152(3): 418-25.
[170] Song N, Liu W, Tu Q, Liu R, Zhang Y, Wang J. Preparation
and in vitro properties of redox-responsive polymeric
nanoparticles for paclitaxel delivery. Colloids Surf B
Biointerfaces. 2011; 87(2): 454-63.
[171] Zhang Z, Lee SH, Feng SS. Folate-decorated poly (lactide-
co-glycolide)-vitamin E TPGS nanoparticles for targeted drug
delivery. Biomaterials. 2007; 28(10): 1889-99.
[172] Sun B, Feng SS. Trastuzumab-functionalized nanoparticles of
biodegradable copolymers for targeted delivery of docetaxel.
Nanomed Nanotech Biol Med. 2009; 4(4): 431-45.
[173] Anbharasi V, Cao N, Feng SS. Doxorubicin conjugated to D!
α!tocopheryl polyethylene glycol succinate and folic acid as a
prodrug for targeted chemotherapy. J Biomed Mater Res A.
2010; 94(3): 730-43.
[174] Mi Y, Zhao J, Feng SS. Vitamin E TPGS prodrug micelles for
hydrophilic drug delivery with neuroprotective effects. Int J
Pharm. 2012; 438(1): 98-106.
[175] Mi Y, Zhao J, Feng SS. Targeted co-delivery of docetaxel,
cisplatin and herceptin by vitamin E TPGS-cisplatin prodrug
nanoparticles for multimodality treatment of cancer. J Control
Release. 2013; 169(3): 185-92.
... Vitamins are organic molecules necessary to act as coenzymes, antioxidants, or regulators of gene expression [1]. Vitamins cannot be produced by the body but are mainly obtained from the diet in food or supplements [1]. ...
... Vitamins are organic molecules necessary to act as coenzymes, antioxidants, or regulators of gene expression [1]. Vitamins cannot be produced by the body but are mainly obtained from the diet in food or supplements [1]. Vitamin supplements are commonly used by the population and are frequently administered as a complement to chemotherapies. ...
... Vitamin supplementation as a supportive therapy is very common feature in many cancer patients [1,2]. However, the benefits vs. the harms of taking these supportive medicines are still in serious debate [2], especially in cancer patients undergoing a main chemotherapy [4,21]. ...
Article
Many cancer patients receive their classical therapies together with vitamin supplements. However, the effectiveness of these strategies is on debate. Here we aimed to evaluate how vitamin E supplementation affects the anticancer effects of interferon (IFN-α) using an early-model of liver cancer development (initiation-promotion, IP). Male Wistar rats subjected to this model were divided as follows: untreated (IP), IP treated with recombinant IFN-α-2b (6.5 × 10⁵ U/kg), IP treated with vitamin E (50 mg/kg), and IP treated with combination of vitamin E and IFN-α-2b. After treatments rats were fasted and euthanized and plasma and livers were collected. Combined administration of vitamin E and IFN-α-2b induced body weight drop, increased liver apoptosis and low levels of hepatic lipid levels. Interestingly, vitamin E and IFN-α-2b combination also induced an increase in altered hepatic foci number, but not in size. It seems that vitamin E acts on its antioxidant capability in order to block the oxidative stress induced by IFN-α-2b, blocking in turn its beneficial effects on preneoplastic livers, leading to harmful final effects. In conclusion, this study shows that vitamin E supplementation in IFN-α-2b-treated rats exerts unwanted effects; and highlights that in spite of being natural, nutritional supplements may not always exert beneficial outcomes when used as complementary therapy for the treatment of cancer.
... In general, vitamins A, D, E, and K are classified as lipid-soluble, while vitamins B complex and C are water-soluble. These vitamins can be obtained through the diet as human cells are incapable of synthesizing these micronutrients to meet the body's needs [10]. The anticancer properties of lipidsoluble vitamins have been evaluated in GBM cells as these vitamins are able to cross the blood-brain barrier (BBB) to access these tumors. ...
Article
Full-text available
Glioblastoma (GBM), a highly lethal form of adult malignant gliomas with little clinical advancement, raises the need for alternative therapeutic approaches. Lipid-soluble vitamins have gained attention in malignant brain tumors owing to their pleiotropic properties and their anti-cancer potential have been reported in a number of human GBM cell lines. The aim of this paper is to systematically review and describe the roles of various biomarkers regulated by lipid-soluble vitamins, such as vitamins A, D, E, and K, in the pathophysiology of GBM. Briefly, research articles published between 2005 and 2021 were systematically searched and selected from five databases (Scopus, PubMed, Ovid MEDLINE, EMBASE via Ovid, and Web of Science) based on the study’s inclusion and exclusion criteria. In addition, a number of hand-searched research articles identified from Google Scholar were also included for the analysis. A total of 40 differentially expressed biomarkers were identified from the 19 eligible studies. The results from the analysis suggest that retinoids activate cell differentiation and suppress the biomarkers responsible for stemness in human GBM cells. Vitamin D appears to preferentially modulate several cell cycle biomarkers, while vitamin E derivatives seem to predominantly modulate biomarkers related to apoptosis. However, vitamin K1 did not appear to induce any significant changes to the Raf/MEK/ERK signaling or apoptotic pathways in human GBM cell lines. From the systematic analysis, 12 biomarkers were identified that may be of interest for further studies, as these were modulated by one or two of these lipid-soluble vitamins.
... Fruits are rich in bioactive compounds like vitamin C and flavonoids. Vitamin C is a cofactor of enzymes and a scavenger of active oxygen, which can inhibit the formation of carcinogen nitrosamines in the stomach and reduce the oxidative damage of the gastric mucosa (Jain et al. 2017). Flavonoids are secondary metabolites of plants, widely found in vegetables, fruits, pasture, and medicinal plants, with antioxidant, antiinflammatory, free radical scavenging, immunomodulatory functions, and also promote the absorption of vitamin C (Hazafa et al. 2020), thus reducing the occurrence of GC. ...
Article
Full-text available
Background Several systematic reviews and meta-analyses evaluated the associations between dietary factors and the incidence of gastric cancer (GC). Objectives To evaluate the strength and validity of existing evidence, we conducted an umbrella review of published systematic reviews and meta-analyses that investigated the association between diets and GC incidence. Methods We searched the PubMed, Embase, and Cochrane databases for systematic reviews and meta-analyses of prospective cohort studies investigating the association between dietary factors and GC risk. For each association, we recalculated the adjusted summary estimates with their 95% confidence interval (CI) and 95% prediction interval (PI) using a random-effects model. We used the I² statistic and Egger’s test to assess heterogeneity and small-study effects, respectively. We also assessed the methodological quality of each study and the quality of evidence. Results Finally, we identified 16 meta-analyses that described 57 associations in this umbrella review. Of the 57 associations, eight were statistically significant using random-effects, thirteen demonstrated substantial heterogeneity between studies (I² > 50%), and three found small-study effects. The methodological quality of meta-analyses was classified as critically low for two (13%), low for thirteen (81%), and only one (6%) was rated as high confidence. Quality of evidence was rated high for a positive association for GC incidence with a higher intake of total alcohol (RR = 1.19, 95% CI 1.06–1.34) and moderate-quality evidence to support that increased processed meat consumption can increase GC incidence. Three associations (total fruit, vitamin E, and carotenoids) were determined to be supported by low-quality evidence, and two (pickled vegetables/foods and citrus fruit) were supported by very low-quality. Conclusions Our findings support the dietary recommendations for preventative GC, emphasizing lower intake of alcohol and foods preserved by salting. New evidence suggests a possible role for total fruit, citrus fruit, carotenoids, and vitamin E. More research is needed on diets with lower quality evidence. Registration number CRD42021255115.
... Hence, active targeting strategies have been used to overcome these obstacles. A nanocarrier surface has been modified using a ligand that is identified by the receptors (overexpressed on cancer cells) [9][10][11][12]. The drug is attached to the receptor and internalized by receptormediated endocytosis, resulting in the enhanced localization of bioactive molecules to target sites [13][14][15]. ...
Article
Introduction: Breast carcinoma (BC) is one of the most frequent causes of cancer-related death among women, which is due to the poor response to conventional therapy. There are several complications associated with monotherapy for cancer, such as cytotoxicity to normal cells, multidrug resistance (MDR), side effects, and limited applications. To overcome these challenges, a combination of chemotherapy and immunotherapy (monoclonal antibodies, anticancer vaccines, checkpoint inhibitors, and cytokines) has been introduced. Drug delivery systems (DDSs) based on nanotechnology have more applications in BC treatment owing to their controlled and targeted drug release with lower toxicity and reduced adverse drug effects. Several nanocarriers, such as liposomes, nanoparticles, dendrimers, and micelles, have been used for the effective delivery of drugs. Areas covered: This article presents opportunities and challenges in BC treatment, the rationale for cancer immunotherapy, and several combinational approaches with their applications for BC treatment. Expert opinion: Nanotechnology can be used for the early prognosis and cure of BC. Several novel and targeted DDSs have been developed to enhance the efficacy of anticancer drugs. This article aims to understand new strategies for the treatment of BC and the appropriate design of nanocarriers used as a combinational DDS.
... Chemoradiotherapy remains the mainstay of treatment for patients with advanced EC. The most common complications during chemoradiotherapy in EC patients include weight loss, malnutrition, bone marrow suppression, electrolyte disturbances, hypoproteinemia and decreased quality of life [4][5][6][7]. Multiple vitamins are involved in the pathogenesis, progression and prognosis of tumors and are closely related to the tumor microenvironment. ...
Article
Background: Many studies have investigated the relationships between vitamins and esophageal cancer (EC). Most of these studies focused on the roles of vitamins in the prevention and treatment of EC, and few studies have examined the changes in vitamin nutritional status and their influencing factors before and after chemotherapy for EC. Chemotherapy may have a considerable effect on EC patients' vitamin levels and hematological indicators. Aim: To research the nutritional status of multiple vitamins in EC patients during chemotherapy and to assess its clinical significance. Methods: EC patients admitted to our center from July 2017 to September 2020 were enrolled in this study. Serum concentrations of nine vitamins (A, D, E, B9, B12, B1, C, B2 and B6), hemoglobin, total protein, albumin, blood calcium, blood phosphorus concentrations and body mass index (BMI) were measured in all EC patients. The changes in nine vitamins, hematological indicators and BMI were compared before and after two cycles of chemotherapy. The possible influential factors were analyzed. Results: In total, 203 EC patients receiving chemotherapy were enrolled in this study. Varying degrees of vitamin A, D, C and B2 deficiency and weight loss were found in these patients, and the proportions of vitamin B2 and vitamin C deficiencies increased significantly after chemotherapy (both P < 0.05). Serum concentrations of vitamins A, C, B2 and B6 and BMI before and after chemotherapy were statistically significant (all P < 0.05). Multivariate analysis showed that vitamin A levels significantly differed between male and female EC patients, whereas vitamin D concentration significantly differed in EC patients in different stages (all P < 0.05). Correlations were observed between the changes in serum concentrations of vitamin A and C before and after two cycles chemotherapy and the change in BMI (P < 0.05). Hemoglobin, total protein, serum albumin and blood calcium concentrations significantly decreased in EC patients after chemotherapy (all P < 0.05), while the blood phosphorus level significantly increased after chemotherapy (P < 0.05). Using the difference in vitamin concentrations as the independent variables and the difference in BMI as the dependent variable, logistic regression analysis revealed statistically significant differences for vitamin A, vitamin D and vitamin C (F = 5.082, P = 0.002). Conclusion: Vitamin A, D, C and B2 were mainly deficient in patients with EC during chemotherapy. Multivitamin supplementation may help to improve the nutritional status, chemotherapy tolerance and efficacy.
... In this context, food intake becomes an essential player in slowing or increasing the risk for breast cancer development. A diversity of approaches involving food (e.g., nuts, veggies, fruits, spices) [2][3][4][5], food components (e.g., fat, vitamins, minerals) [6,7] and dietary supplements (e.g., quercetin, curcumin, resveratrol) [8][9][10] are recognized as complementary methodologies in cancer prevention and treatment. It is recognized that the maternal diet during pregnancy impacts the mammary gland health of offspring in animal models [11][12][13][14][15]. ...
Article
Full-text available
Purpose Omega-3 fatty acids have been shown to reduce the incidence and slow the growth of mammary gland cancer in rodent models. Since exposure to dietary components during the critical developmental times of gestation and lactation may alter risk for mammary gland cancer in females, we tested whether exposure to increased levels of long-chain omega-3 fatty acids from fish oils would be preventive or promotional to mammary gland cancer in the offspring. Methods Normal SV129 female mice were fed AIN 76 diets containing either 10% corn oil (control, 50% omega 6, n-6) or 5% of an omega-3 (n-3) fatty acid concentrate (fish oil 60% n-3) + 5% canola oil (10% n-3 + 20% n-6). Females were then mated with C(3)1 TAg transgenic mice. At weaning (3 weeks), pups were randomized to either the corn (C) or fish oil (F) diet, 15–17 mice per group. Four experimental groups were generated: FF, FC, CF and CC. Tumor incidence and multiplicity were assessed at the following time points 120, 130 and 140 days of age. A panel of genes encoding signal transduction proteins were analyzed in mammary glands at 130 days. Results Mice never exposed to fish oil (CC group) had a significantly higher incidence and multiplicity of mammary gland tumors than mice exposed to fish oil throughout life (FF group). Mice exposed to fish oil during a portion of life (CF or FC) had intermediate tumor incidences and multiplicities. Results also indicate that maternal consumption of fish oil increased the expression of genes associated with immune system activation (Ccl20, Cd5, Il2, Lef1, Lta). Conclusions Adequate omega-3 fatty acids in the maternal diet may reduce the risk for mammary gland cancer in the offspring. If humans make dietary change by consuming more omega-3 fat instead of corn oil with 0% omega 3 fat, breast cancer may be reduced in the next generation.
Chapter
The major anticancer drugs used for cancer therapy show nonspecificity, wide biodistribution, a short half-life, a low concentration in tumor tissue, and systemic toxicity. The biodegradable polymer can be used as an approach that acts as a drug carrier, offering a targeted drug delivery and increasing the drug payload to the tumor tissues and cells. It also enhances biocompatibility, provides prolonged release of the drug allowing controlled and sustained release, and minimizes systemic toxicity. This chapter focuses on targeted drug delivery through a stimuli-responsive drug carrier that releases its payload at the specified site and on demand in response to an external stimulus. It also emphasizes various applications of biodegradable polymers in breast cancer, lung cancer, colon cancer, and uterine cancer with special emphasis on theranostic applications. Some patents on biodegradable polymer-based anticancer drug delivery are also discussed in this chapter.
Chapter
Cancer is the leading cause of death worldwide. This disease is described as accelerated and uncontrolled cell multiplication. In recent decades, chemoprevention has been advocated to reduce the risk of cancer or prevent its recurrence. An example of chemopreventives is antioxidant vitamins, which inhibit angiogenesis and cancer cell metastasis. In addition, vitamin C, vitamin D and vitamin E decrease the side effects caused by chemotherapy during cancer treatment. This review provides a complete update on the therapeutic potential of vitamins C, D and E against cancer. Unfortunately, most studies suggest the need to conducting rigorous clinical trials to confirm the benefits of these vitamins. In addition, chemopreventive regimens should be adjusted for a greater range of cancer types.
Article
Full-text available
Vitamin B12 (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical B12 deficiency with classic haematological and neurological manifestations is relatively uncommon. However, subclinical deficiency affects between 2.5% and 26% of the general population depending on the definition used, although the clinical relevance is unclear. B12 deficiency can affect individuals at all ages, but most particularly elderly individuals. Infants, children, adolescents and women of reproductive age are also at high risk of deficiency in populations where dietary intake of B12‑containing animal-derived foods is restricted. Deficiency is caused by either inadequate intake, inadequate bioavailability or malabsorption. Disruption of B12 transport in the blood, or impaired cellular uptake or metabolism causes an intracellular deficiency. Diagnostic biomarkers for B12 status include decreased levels of circulating total B12 and transcobalamin-bound B12, and abnormally increased levels of homocysteine and methylmalonic acid. However, the exact cut-offs to classify clinical and subclinical deficiency remain debated. Management depends on B12 supplementation, either via high-dose oral routes or via parenteral administration. This Primer describes the current knowledge surrounding B12 deficiency, and highlights improvements in diagnostic methods as well as shifting concepts about the prevalence, causes and manifestations of B12 deficiency.
Chapter
Full-text available
Safe and effective cancer therapy demands a suitable nanocarrier which can target cancer cells in a selective manner. With the tremendous growth in nanotechnology, liposomes among various competing nanocarriers have shown promising milestones in cancer therapy. Liposomes revived the “magic bullet concept” in terms of safe and efficacious delivery of bioactive(s) to tumor site. Liposomes offer outstanding capabilities such as carrying capacity (both hydrophilic and hydrophobic bioactives) and possibilities for compositional and surface modifications. This chapter covers critical considerations for development of liposomes to target cancer cells with the use of Enhanced Permeability and Retention (EPR) effect and selective ligands such as folate, transferrin, and peptides etc. The gold standard to render long circulatory effects to conventional liposomes i.e., PEGylation has also been discussed in this chapter to resolve safety issues primarily concerned with active targeting approaches. Recent advances in fabrication of liposomes have also been summarized here including stimuli responsive and multifaceted approaches of cancer targeting.
Article
Full-text available
Topotecan (TPT), a potent anticancer camptothecin analog, is well described for the treatment of ovarian cancer, but has also anticancer activity against small-cell and non-small-cell lung cancer, breast cancer, and acute leukemia. Various nanocarriers, including liposomes, have been exploited for targeted delivery of TPT. However, there are a number of challenges with TPT delivery using TPT liposomes (TLs), such as low encapsulation efficiency, physiological pH labile E ring (hydrolysis), accelerated blood clearance, multidrug resistance, and cancer metastases. This review discusses these problems and the means to overcome them, including modification of TLs using zwitterionic poly(carboxybetaine), prolongation in dosing interval (long-term therapy), and modified liposomal encapsulation techniques including active loading methods. We also explore engineered TLs (surface and integral modifications) such as PEGylated TLs, ligand-anchored TLs, and stimuli-sensitive TLs. Further, potential applications, manifestations at the molecular level, patents granted, and preclinical and clinical outlook for TLs are discussed.
Article
Full-text available
Microparticulate drug delivery systems have been explored across the globe due to their various advantages. In 1987, Won developed microsponge systems (Micsys), also known as solid-phase porous microspheres, having numerous interconnected voids, which serve as non-collapsible residence for bioactive compounds. A Micsys particle ranges from 5 to 300 μm in size and shows a wide range of entrapment efficiency with desired release rates. This topical drug delivery system bestows a controlled release of bioactive compounds into the skin with reduced systemic side effects. Currently, the application fields of this promising system include oral, ocular, pulmonary, and parenteral delivery of bioactive compounds. In the present review, we summarize the updated biomedical application potential of Micsys as an effective drug-delivery vector, including an in-depth explanation of the drug-release kinetic models and drug-release mechanisms. We also discuss different techniques used to prepare a Micsys, along with their advantages and disadvantages. Moreover, in this review, we report a plethora of Micsys details, such as drug candidates and polymers, exploited in this field, along with marketed formulations, characterization methods, clinical perspectives, and patents received. This assembly of detailed literature summaries will contribute to future advances in the development of porous carriers.
Book
In the past five years, a surprising and intense resurgence in interest in vitamins and other micronutrients and their role in health and dis­ ease has occurred. The recognition has emerged that vitamins not only are essential for life ·in that severe nutritional deficiencies occur in their absence, but that these compounds may also serve as natural inhibitors of cancer. Synthetic alterations of the basic vitamin A mole­ cule have also resulted in the production of compounds that are more potent as anticancer agents than the natural substance and may have substantial therapeutic activity as well. Whether other vita­ mins can be changed or altered to produce a better anticancer effect than the native compound has been little explored to date, but should be a fruitful pursuit for future study. In our concluding remarks to the First International Conference in 1982, we speculated that rapid advances in our understanding of vi­ tamins would occur in the next few years and that large-scale inter­ vention trials of vitamins as preventive agents in defined human pop­ ulations would be started. This anticipated generation of data on vitamins and their interactions has proceeded rapidly and the impor­ tance of interactions between vitamins and other micronutrients in the prevention setting has become better appreciated. Currently, more than 25 intervention trials with a variety of target populations using vitamins and other micronutrients have been started, but it re­ mains too early for meaningful analysis of the results to date.
Chapter
Most anticancer agents are poorly water soluble and highly potent by nature, leading to nonselective devastation of tumor, as well as normal healthy cells; this poses an obstinate challenge in safe and effective tumor chemotherapy. To get the better of this debilitating problem, liposomes have emerged as revolutionary cargoes, in last few decades, with successful rates on the rise in tumor targeting. Their extraordinary capability to carry both hydrophilic and hydrophobic bioactives in separate domains of residence and amenability to surface and compositional engineering destine this vesicular system to come true the “magic bullet concept” which was enunciated by the great biologist Paul Ehrlich. Enhanced permeability and retention effect and tumor specific ligands mediate passive targeting and active targeting to tumors, respectively. The stealth effect attributed to PEGylation in liposomes has opened up new horizons in prolonged drug delivery, and proved to be a promising tactic to solve safety issues associated with active targeting principles. Current scenarios in liposomes fabrication techniques bring forth environmentally responsive features (pH, temperature, and photosensitivity, etc.) to facilitate enhanced localization at the tumor site, in addition to targeting capabilities. This chapter sums up the drug targeting potential of the engineered liposomes, with contemporary trends in the field of liposomal research.
Article
The aim of our experiment was to evaluate the anticancer effect of bamboo salt (BS) on C57BL/6 mice in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon cancer model. BS, solar salt, and purified salt were evaluated for their protective effects during AOM/DSS-induced colon carcinogenesis in C57BL/6 mice. BS, especially after baking for nine separate intervals (BS9x), suppressed colon carcinogenesis in the mice. BS9x decreased colon length shortening, weight-to-length ratios, and tumor counts. Pathological evidence from histological evaluation by hematoxylin and eosin staining also revealed suppression of tumorigenesis. BS9x lowered serum levels of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) to close to those of the Normal group. Additionally, BS9x suppressed colon mRNA expression of proinflammatory factors and significantly regulated mRNA levels of the apoptosis-related factors, Bax and Bcl-2, and the cell cycle-related genes, p21 and p53. Additionally, immunohistochemistry showed that BS promoted p21 expression in the colon. Taken together, the results indicate that BS exhibited anticancer efficacy by modulating apoptosis- and inflammation-related gene expression during colon carcinogenesis in mice, and repetition in baking cycles of BS enhanced its anticancer functionality. © Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition 2016.
Article
Incidence of lung cancer is decreasing among men and increasing among women in developed countries and also in Korea. However, mortality of lung cancer is still the highest among male cancers. Smoking is one of the group 1 carcinogens for lung cancer development, but its prognostic effect on lung cancer survival is not well established. Beta-carotene supplement increased the risk of lung cancer among smokers but the role of multivitamin supplement on the risk and survival of lung cancer is unclear either. We aimed to evaluate the association between smoking and multivitamin use on lung cancer survival by sex. We interviewed 910 pathologically confirmed lung cancer patients who were diagnosed between 2010 and 2012 in Samsung Medical Center. Questionnaire included current smoking status, age at first smoking, daily smoking amount, alcohol intake, past medical history, and multivitamin use. Pathological type, stage, and treatment information was collected from the electronic medical records. We followed the patients until December 31, 2012. Hazard Ratios (HR) and 95% Confidence Intervals (CI) were estimated using Cox's proportional hazard model (SAS9.4). We found significant difference in age at diagnosis, pathological type and stage between male and female patients; Female patients were younger, smoked less, used more multivitamin, and had more adenocarcinoma and earlier stage cancer than male patients. Smoking increased the risk of lung cancer mortality among female patients only. HR for lung cancer mortality for those who smoked more than 40 pack-years compared to those who never smoked was 5.64 (95%CI = 1.43, 22.28) in women and 1.17 (95%CI = 0.61, 2.26) in men (p-interaction = 0.01) when adjusted for age, stage, and pathologic type. Multivitamin use also increased the risk of lung cancer mortality among female patients only. HR for lung cancer mortality for multivitamin users was 4.14(95%CI = 1.77, 9.73) in women and 1.46 (95%CI = 0.71, 3.00) in men (p-interaction = 0.17). The association between multivitamin use and lung cancer mortality was strongest among female non-smokers (HR = 4.10, 95%CI = 1.72, 9.77). In conclusion, smoking and multivitamin use worsen the survival of female lung cancer. Prognostic effect of multivitamin use may be stronger among non-smokers. Citation Format: Mi Yang, Hyun-Kyung Oh, Young Mog Shim, Myung-Hee Shin. Differential prognostic effect of smoking and multivitamin use on lung cancer survival by sex. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3418.