Keywords
Cancer - Vitamin D - Vitamin D3 (1 - 25-dihydroxycholecalciferol - calcitriol)
Introduction
Vitamin D, unlike other vitamins, synthesis by the human body following exposure to
ultraviolet rays. Hence, it is also called “Sunshine Vitamin.” It is a fat-soluble
vitamin and stored in the body's fatty tissue, which maintains serum calcium and phosphorus
level. Vitamin D deficiency is considered the most prevalent nutritional deficiency
in both developed and developing countries. Vitamin D deficiency is fast becoming
pandemic, a global and national health concern. However, the bigger concern is that
the population at large is not even aware of Vitamin D deficiency and its consequences.
One-third of all cancers could be attributed to dietary deficiency.
Cancer has a poor prognosis despite improvements in surgery, chemotherapy, and radiotherapy
and has increased the prevalence of morbidity and mortality. Cancer chemoprevention
plays a very important role in preventing the deadly devastating disease of our society.
In this fast-moving competitive world with sedentary lifestyle, habits have been changed.
We are consuming adulterated food with less nutritious. Most of the time we stay indoors
with less physical activities leads to obesity and because of workload results in
decreased exposure to sunlight. Use of sunscreen lotions, clothing to protect from
sunlight, air pollution, and latitude all these factors which leads to decrease in
Vitamin D (1,25-dihydroxyvitamin D) synthesis. The active form of Vitamin D in the
body is 1,25-dihydroxyvitamin D or calcitriol, which can be made from either Vitamin
D2 or Vitamin D3 after exposure to ultraviolet B (UVB) sunlight or ingested in the
diet. To make the active form, Vitamin D2 and Vitamin D3 are modified in the liver
to produce 25-hydroxyvitamin D (25 [OH] D), which travels through the blood to kidneys,
where it is modified further to make 1,25-dihydroxyvitamin D. Vitamin D is involved
in a number of processes that are essential for good health, including the followings:
-
It helps improve muscle strength and immune function
-
It helps to reduce inflammation
-
It promotes the calcium absorption from the small intestine
-
It helps maintain adequate blood levels of the calcium and phosphate needed for bone
formation, mineralization, growth, and repair.[1],[2],[3] It can also be obtained through the diet, but very few foods naturally contain vitamin
D. These foods include oily fish such as salmon, mackerel and sardine, fish liver
oil, and eggs. Smaller amounts are found in meat and cheese. The most dietary Vitamin
D comes from fortified foods such as milk, juices, yogurt, bread, and breakfast cereals.
Vitamin D also can be obtained through dietary supplements. Dietary supplements and
fortified foods usually contain either Vitamin D2 or Vitamin D3.[2]
Role of Vitamin D in prevention of cancer
Women with higher solar UVB exposure in the third National Health and Nutrition Examination
Survey had only half of the incidence of breast cancer as those with lower solar exposure,[4] whereas men in another national survey who had higher residential solar UVB exposure
had only half the incidence rate of fatal prostate, colorectal, and breast cancer.[5] Fifty percent reduction in head and neck cancer after administration of Vitamin
D3-treated animals.[11] The strong association of Vitamin D deficiency in diabetes, immunity, asthma, infections,
high blood pressure, neuromuscular function, cancer, etc., was noted in contrast with
the fact that Vitamin D receptors present in various organs and tissues of the human
body, maintaining Vitamin D levels in blood above 30 ng/ml may ensure normal functioning
of the body organs, and protect many from suffering from chronic ailments.[6],[7],[10] Vitamin D status in relation to 25(OH) D levels according to the US endocrine society
classification as follows.[7]
Vitamin D deficiency, if serum level of 25 (OH) D level <20 ng/ml, Vitamin D insufficiency
if serum level of 25 (OH) D level <21–29 ng/ml, Vitamin D sufficiency if serum level
of 25 (OH) D level> 30 ng/ml, and Vitamin D toxicity if serum level of 25 (OH) D level>
150 ng/ml. The term deficiency of Vitamin D does not necessarily suggest explicit
disease clinically, rather it means an increased risk for certain diseases and that
also explains the seeming paradox that individuals who are ostensibly healthy today
may nevertheless be deficient. As these diseases are multifactorial etiology, deficiency
of Vitamin D, rather than being directly causal, acts by impeding the ability of tissues
to adequately deal with physiological and pathological stimuli. However, these diseases
will occur in the presence of optimum Vitamin D status; their risk will be lowered.[8] Improved understanding of the detrimental effects of Vitamin D insufficiency before
the appearance of rickets led to a growing interest in these lesser degrees of Vitamin
D deficiency and diagnosing this prerachitic, subclinical Vitamin D deficiency is
important for non-skeletal health benefits.[23] Exposure of arms and legs to sunlight for 10–15 min between the hours of 10:00 am
and 3:00 pm 3–4 times a week for people of dark color, longer, and more frequent exposure
is recommended up to 30-min daily.[8]
The institute of medicine was able to set a recommended daily allowance (RDA) for
Vitamin D. The RDA of Vitamin D for children and adults up through age 70 is 15 μg
(equal to 600 international units [IU]) per day. The RDA is 20 μg (800 IU) a day for
adults older than 70. The safe upper limit for adults was set at 100 μg (4000 IU)
per day.[9] Serum or plasma 25 (OH) D is the accepted biomarker for short-term accurate assessment
of Vitamin D status, can arise from hydroxylation of either Vitamin D2 or D3, it is
recognized that many people have unexpectedly low levels. For those people, there
are questions about how much Vitamin D it takes to raise the body's stores of it to
healthy levels. It has been estimated that for every 100 IU of Vitamin D ingested;
there is an increase in the blood level of 25 (OH) D of 1 ng/ml (2.5 nmol/L). Adequate
exposure to UVB radiation or sunlight is more effective in raising blood levels of
25 (OH) D than 1000 IU Vitamin D3 taken daily for adults of most skin types.[12],[13]
Vitamin D induces anti-inflammatory by suppression of prostaglandin action through
suppression of cyclooxygenase 2 expression, stress kinases, nuclear factor KB (NF-KB)
signaling, and increasing tissue inhibitor of metalloproteinases 1 and E-cadherin
response. Antiproliferation by decrease in cyclin-dependent kinases, cyclins, MYC
and RB expression, and increase in P21 and P27 expression and intracellular kinase
pathway modulations such as MAPK, ERK, P38 and P13 pathways. Apoptosis induction by
inhibition of NF–kB signaling increases the expression of BAX proapoptotic gene and
decrease in BCL-2 antiapoptotic gene. Induce differentiation by increase expression
of casein, lipids, prostate-specific antigen, E-cadherin differentiation factors,
adhesion of cancer, and normal cells through the regulatory mechanism. In addition,
it affects growth factors by inhibiting IGF, EGF, and increased expression of growth
inhibitor TGF-Beta, regulation of cell division, cytokine synthesis, signaling cell
cycle control, and apoptosis pathway. Antiangiogenesis by decrease the activity of
hypoxia-inducible factor alpha, vascular endothelial growth factor, interleukin-8,
tenascin C, and prostaglandin E2 levels. Anti-invasion and metastasis by decreasing
expression of matrix metalloproteinases-9, integrins, and plasminogen activator.[14] Calcitriol decreases the expression of aromatase, the enzyme that generally catalyzes
the peripheral estrogen synthesis from androgens as well as in cancer tissue. Calcitriol
downregulates the expression of estrogen receptors and further reduces estrogen signaling
in cancer cells and its anti-inflammatory actions might play a role in for the prevention
for cancer.[15],[16]
A pooled analysis of two studies with 880 cases and 880 controls demonstrated that
individuals with serum 25 (OH) D3 of approximately 52 ng/ml had a 50 percent lower
risk of breast cancer than those with levels of 13 ng/ml.[17] A case–control study on 1394 postmenopausal breast cancer patients and 1365 controls
confirmed that the 25 (OH) D level was significantly associated with lower breast
cancer risk, particularly at levels above 20 ng/ml.[18] Another population-based randomized controlled trial found that calcium plus Vitamin
D supplementation decreased cancer incidence as a secondary outcome and the dose of
1100 IU/day increased serum 25 (OH) D from 29 to 38 ng/ml. After 4 years of treatment,
the supplemented group showed a 60% lower risk of developing cancer than the placebo
group.[19] The study has to confirm the benefit of using calcium and Vitamin D supplement than
using Vitamin D supplement alone. Women in the women's health initiative who were
Vitamin D deficient (25 (OH) D <12 ng) had a 253% increased risk for developing colorectal
cancer during the 8 years of the study compared with women who were Vitamin D sufficient
at the beginning of the study.[20]
Potential toxic effects of Vitamin D overdosage, such as bone demineralization, hypercalcemia,
hypercalciuria, or nephrocalcinosis with renal failure are encountered rarely, only
when the daily dose exceeds 10,000 IU of Vitamin D on a chronic basis. However, no
known health risks are associated with dosages of Vitamin D in normal range of intake
2000 IU/day which is affordable in preventing many types of cancer.[21],[22] In patients with liver, kidney, and gastrointestinal disease, people taking medicines
that affect Vitamin D (1,25-dihydroxyvitamin D) levels such as certain antiepileptic
medication, rifampicin, isoniazid, and glucocorticoids and people with dark skin are
more predispose to many types of cancer.[23]
A clinical trial comprised 16 patients with newly diagnosed head and neck squamous
cell carcinoma (HNSCC) being untreated and 16 patients being treated with 1,25(OH)2
D3(Vitamin D3) during a 3-week interval between cancer diagnosis and surgical treatment.
The HNSCC tissues of patients who received treatment with 1,25(OH)2D3(Vitamin D3)
had increased levels of CD4+ T-cells. The results of this study demonstrate that the
patients treated with 1,25(OH)2D3(Vitamin D3) had a lengthier time to tumor recurrence
compared with patients who were not treated before the surgery.[24],[25],[26]
Vitamin D has a complex interaction between parathyroid hormone and calcium, diet
and genetic modification need to be understood. Regular estimation of Vitamin D status
by serum 25 (OH) D levels is important for prevention and treating effects of extraskeletal
effects caused by subclinical Vitamin D deficiency. Certain lifestyle modifications
with supplementation or fortification of food can go longway to our main motto in
prevention is better than no cure for this enigmatic disease in later stages.
Conclusion
Vitamin D is the name given to a group of fat-soluble prohormones. Two major forms
of vitamin D are vitamin D2 or ergocalciferol and vitamin D3 or cholecalciferol is
an active form of vitamin D. Vitamin D is a naturally occurring vitamin and receptors
of Vitamin D are present in all cell types of our body to perform various functions.
Eighty percent of populations are deficient in Vitamin D because of change in lifestyle.
Vitamin D deficiency is a global health concern predisposes to various diseases such
as cancer. Vitamin D helps in prevention of various cancers by reducing inflammation,
antiapoptotic, and antiproliferative and decreasing aromatase activity, but there
is no universal protocol for Vitamin D administration depending on patient age, weight,
and location.
