REVIEW

Importance of vitamin D in management

Muhammad Irfan1, Muhammad Sajid Hamid Akash1, Syed Aun Muhammad2, Maryam Rafique Ibrahim1 and Muhammad Imran Qadir2* 1Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, 2Institute of Molecular Biology & , Bahauddin Zakariya University, , Pakistan

Abstract: Vitamin D is essential element for growth and development of bones. The receptor of the metabolite of vitamin D known as “nuclear calcitriol” have been identified in tissues and is responsible for playing a wide range of biological processes. Calcidiol [25(OH) D3] corresponds to the storage space and the chief flowing metabolite of vitamin D3. Calcitriol 1-α-25-dihydroxycholecalciferol is formed in the kidney. Deficiency of vitamin D and lack of sun exposure has been found to cause unceasing illnesses together with various lethal . At cellular level the mechanism of anticancer action of vitamin D has not been entirely implicated. For th e setting off and regulation of particular genes, calcitriol-VDR-RXR complex attach to definite DNA fragments called as vitamin D response elements (VDREs). After binding with VDR, calcitriol performs its function by regulating the function of over and abo ve 60 genes providing direction for antiproliferative, prodifferentiating and antimetastatic effects on cells to result in antiangiogenic property. Vitamin D deficiency is evaluated as level of calcidiol less than 20ng/mL, shortage to the level of 21-29 ng/mL, and adequacy level is 30ng/mL.

Keywords: Vitamin D, Calcidiol, Calcitriol, Angiogenesis, Apoptosis, Cancer, Cell Proliferation

INTRODUCTION Physiology Vitamin D fit in to the foursome of fat soluble vitamins Vitamin D is renowned as being vital for healthiness of (A, D, E and K). This accounts for its allocation mainly in bones (Giovannucci et al., 2006).Vitamin D plays a role adipose tissue and its very measured yielding pace. It is a of true hormones, as it belongs to a set of prohormones secosteroid with a ring structure comparable to that are actually fat soluble and in the body they form a excluding the broken C-C bond in the B ring. number of biologically active metabolites, which circulate Vitamin D exists in two major forms: vitamin D2, is the in the blood and modify the activities of various cell types first one also called as calciferol, formed by the - both calcemic and noncalcemic (Stolzenberg-Solomon irradiation of yeast (Kostner et al., 2009). And the second et al., 2009). The receptors of the metabolite of vitamin D is vitamin D3 (cholecalciferol), which is most important known as nuclear calcitriol have been identified in both and is a resultant obtained by photo conversion of 7- tissues which when get activation signals not only have hydrocholesterol in the skin when exposed to sunlight or the power over calcium metabolism, besides this they artificial ultraviolet rays and fish liver oil provides huge elicit a broad range of biological responses, which interns amounts of vitamin D3. Lanolin also called wool fat act as controls growth of cells as well as their proliferation, the unprocessed starting material for commercial apoptosis, and execution of immune system. Recently, production of vitamin D . Certainly both D and D are this growth modulating property of calcitriol is subject 3 2 3 accessible in pill form. Dietary sources of vitamin D3 (Bid mattered to extreme research in the ground of cancer et al., 2005) are given in table 1. preclusion and reserve (Angwafo et al., 1998). Biologically Vitamin D is pathetic as compared to D , History 2 3 owning no more than 30% of vitamin D activity. The two Over the past 5 years, a noticeable boost in the quantity of 3 forms (D2 and D3), in the body track same metabolic high-dose vitamin D prescriptions in the United States has pathways. Though, our center of attention in this been observed. Vitamin D has an elongated and attention- evaluation will be largely on D3 because it constitutes the grabbing account which is intimately associated with main contribution and in humans it occurs naturally. rickets, the childhood bone disease. Since the middle of Calcidiol [25(OH)D ] corresponds to the storage space 17th century, the subsistence of vitamin D had been 3 and the chief flowing metabolite of vitamin D3. Clinically supposed but in reality it was not revealed before 1920s its level in the plasma is measured for reviewing the and the chemical structure was explicated after 1932 vitamin D dietary condition of the patient. Calcidiol, (McCollum et al., 1922; Holick et al., 2007). vitamin D2, vitamin D3 have practically no inherent *Corresponding author: e-mail: [email protected] biological action at physiological concentrations (Webb et Pak. J. Pharm. Sci., Vol.32, No.5, September 2019, pp.2203-2211 2203 Importance of vitamin D in cancer management al., 1998). A definite transporter acknowledged as rheumatic arthritis (Sullivan et al., 2005; Heaney et al., a vitamin D-binding protein (DBP) circulates in the body 2003; Dawson-Hughes et al., 2005; Boonen et al., 2006). and helps in travelling away of vitamin D and its mediators. Calcitriol 1-α,25-dihydroxycholecalciferol Actions of vitamin d on vital organs [1,25(OH)2D3] is formed in the kidney when a second Colon, prostate, brain and breast tissues, along with other hydroxyl group is attached to the molecule of calcidiol at organs, over and above the immune cells possess position 1.1α hydroxylase, is a cytochrome P450 enzyme receptors for vitamin D and act in response to the (CYP27B1) which is responsible for the catalization of dynamic type of vitamin D(1,25-dihydroxyvitamin D) this feedback in the kidney. Serum level of calcitriol on (Liu et al., 2006; Li et al., 2003). May be direct or average ranges between 15 and 75pg/mL (Larcombe et indirect way, calcitriol or 1, 25-dihydroxyvitamin D have al., 2008). Manufacturing of calcitriol and its circulating power over above 200 genes, involving genes liable for rank is based on a number of factors; the major one the maintenance of production of insulin, synthesis of belongs to the functioning of 1α-hydroxylase in the renin in kidney, cellular apoptosis, the development and proximal tubule cells of the kidney. Action of this enzyme profusion of muscular cells of heart and vessels, is improved via low calcitriol levels, high parathyroid angiogenesis and cytokines discharge via T cells, and the hormone, low level of calcium and high level of assembly of macrophages against bacterial protein phosphates (Eyleset al., 2005; Fleet et al., 1999). Though, component cathelicidin (Chiu et al., 2004). additionally calcidiol an instant forerunner of calcitriol formation is an important determinant for the activity of Function of vitamin d in immune response 1-α-hydroxylase, whose build in is based on contact to Though, it has been now by and large acknowledged that UV radiation to skin along with ingestion of vitamin D3 a powerful correlation is amid immune system and orally. vitamin D subsists since it‟s been recommended by numerous conclusions: firstly the immune cells of The vitamin D receptor (VDR) is a nuclear transcription humans, particularly those cells which are stimulated bear factor for majority of the recognized actions of calcitriol. the existence of VDR. Secondly, their capacity to form Retinoic acid x-receptor (RXR) in the cell nucleus causes calcitriol, and thirdly, the abundance of T cells is slowed the binding of calcitriol with VDR. For the setting off and down by calcitriol. Additionally, it has been progressively regulation of particular genes, calcitriol-VDR-RXR more clear in current days that calcitriol have a complex attach to definite DNA fragments called as considerable function in varying the roles of the immune vitamin D response elements (VDREs) (Nemere et al., system as it reduces proliferation of normal body cells as 1998; Khanal et al., 2007). well as cancerous cells by stimulating their terminal differentiation (Miller., 2010). When monocytes and Actions & functions macrophages are encountered with lipopolysaccharides In the decades which tagged along its finding, an they stimulate vitamin D receptor gene and therefore irresistible body of medical and laboratory verification results in the augmented formation of vitamin which in recognized its vital function in the persistence of skeletal turn, produces cathelicidin. This helps in wiping out health and calcium balance. Their acknowledged chief infectious organisms. The monocyte or macrophage is action is the upholding of plasma Ca2+ concentration by prohibited from starting this instinctive immune reaction, means of mounting Ca2+ absorption in the intestine, when serum levels of 25-hydroxyvitamin D became lesser moving Ca2+ from bone and decreasing its renal excretion. than 20ng per milliliter (Medzhitov et al., 2007; Kindt et Hence, vitamin D is linked primarily and principally with al., 2007; Bartley et al., 2010). these activities. Conversely, a rapid analysis of the modern journalism discloses that vitamin D is located at Vitamin d deficiency the midpoint of endocrine systems which is responsible Present are several causes of vitamin D deficiency, for differentiation and also for the proliferation of cells, comprising of augmented catabolism, Reduced skin besides a broad variety of additional cellular actions, synthesis, Inadequate bioavailability, Liver failure, enlarging the function of vitamin D ahead of the skeleton Breast-feeding having nutrient insufficient of vitamin D to take account of the neuroendocrine cardiovascular and content and Hyperthyroidism - leading to increased immune systems (DeLuca et al., 2004; Chapuy et al., metabolism of 25-hydroxyvitamin D, Nephrotic syndrome 1992; Dusso et al., 2005). A survey made in such manner - counting for excessive release of vitamin D in urine, and would also be helpful in specifying that deficiency of Heritable disorders - rickets (Reid et al., 1986). vitamin D as well as the genetic changes in the receptors of vitamin D can take most important role in the etiology Epidemiology of a range of persistent disorders which counts cancer, Now- a -days deficiency of Vitamin D is renowned as diabetes, mycobacterium , cardiovascular endemic mainly in the northern hemisphere where sun diseases, and autoimmune diseases such as psoriasis, exposure is minimal and winter is of longer period. multiple sclerosis, systemic lupus erythematous, and Vitamin D distributes preferentially into the adipose 2204 Pak. J. Pharm. Sci., Vol.32, No.5, September 2019, pp.2203-2211 Muhammad Imran Qadir et al tissue with a half-life of more or less 2 months as it is The survey made by 3rd National Health and Nutrition lipophilic. Vitamin D deficiency is evaluated as level of Examination (NHANES III) has exposed that a large calcidiol less than 20ng/mL, shortage to the level of 21- division of the American population have low vitamin D 29ng/mL and adequacy level is 30ng/mL. In recent levels; many other studies verified this fact. The therapeutic practice, these suggested ranges are phenomenon of has also been found in many other progressively getting upward as vitamin D deficiency is including. Middle East and North Africa are also included more and more being concerned with the etiology of an in the parts of the world where people suffer from vitamin intensifying catalog of diseases. Clear vitamin D toxicity D deficiency as their social customs state least skin marked as hypercalcemia and ectopic calcification does spotlight. Causes of vitamin deficiency are numerous and not arise, pending the calcidiol level is well greater than comprise of the following like enclosed standard of 150ng/mL. Though, it is to be decided the enduring safety living, dark skin, high latitude, skin area exposed to UVB of continued high levels (greater than 50ng/mol) given is deficient, chronic kidney disease (CKD), severe liver that the fashion of prescribing vitamin D mega-doses has disease, obesity, aging (abridged capability for become common in recent times. Consequently any photosynthesis). advantage of vitamin D intake has to be balanced in opposition with the risk of known short-term and potential Besides, bone diseases in kids as well as adults, vitamin long-term toxicities (Zittermann et al., 2006). D deficiency has been coupled with a far-reaching diversity of unremitting circumstances with colorectal Table 1: Dietary Sources of Vitamin D3 cancer, diabetes mellitus type II, infectious diseases, hypertension, and autoimmune diseases such as SLE and Cholesterol Vitamin D diabetes mellitus type I (Gorham et al., 2005). Food per 100 g per 100 g Oysters 55 mg 640 IU Depression and schizophrenia Sardines 145 mg 482 IU Vitamin D deficiency has been interrelated to an Cod liver oil 560 mg 10,000 IU augmented occurrence of schizophrenia and depression. Butter 217 mg 57 IU Sustaining vitamin D levels in utero and throughout initial Herring 13.0 mg 670 IU lifespan, maintains the transcriptional activity of the Caviar 585 mg 230 IU vitamin D receptor in brain, which is proven to be Salmon 87 mg 322 IU essential for development and progress of mental Mackerel 94 mg 499 IU functioning in the future life (Zhang et al., 2004).

Whole Egg 424 mg 48 IU Congestive cardiac failure Catfish 82 mg 500 IU Vitamin D deficiency is related to congestive cardiac Shrimp 172 mg 173 IU failure and also responsible for reducing levels of All Plant Foods 0 mg 0 IU inflammatory factors in blood comprising interleukin-10 The relationship between vitamin D &cholesterol content, in addition to, C-reactive protein. Also living at upper definitely is not picture-perfect, however all of the diets leeway intensifies the possibility of cardiovascular disease comprising vitamin D hold significant quantity of cholesterol. and hypertension (Berwick et al., 2005; Jones et al., 1998).

Vitamin d in relation with cancer A Neoplasm or Cancer is “an abnormal mass of tissue the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after the cessation of the stimuli which evoked the change.”

Latitude, sun exposure and chronic diseases It has been experimentally determined that normal exposure to sun is linked with progressive lowering in death rates of certain cancer over and above with decrease in general cancer death rates, which may be correlated with metabolic pathway of vitamin D in the body. The initial indication about the probable connection between cancer and vitamin D deficiency is the study that both the

Fig. 1: Indicators for vitamin D deficiency syndrome occurrence of definite cancers and vitamin D deficiency show a discrepancy by latitude. This is referred to as the Pak. J. Pharm. Sci., Vol.32, No.5, September 2019, pp.2203-2211 2205 Importance of vitamin D in cancer management geographic or ecological factor as it is found to be 2005; Mantell et al., 2000; Cantorna et al., 2004). associated with the north-south sunshine gradient. According to the future and displayed epidemiologic studies specify that levels of 25-hydroxyvitamin D lower Epidemiological survey including 111 countries, a well- than 20ng per milliliter are related to 30 to 50% greater built and productive linkage flanked by latitude and the hazard of episode of breast, colon, prostate cancer, occurrence ratio of lung cancer was observed. All together with high death rates from these cancers. An together there was a converse connection between lung investigation made by Nurses „Health Study cohort rates cancer and the effectual contact to UVB rays. The showed that study of vitamin D ingestion and the peril of instigators concluded that low levels of UVB irradiance colorectal cancer in 1954 men demonstrated a straight are autonomously linked with higher incidence rates of correlation. An observation survey made tells that the lung cancer in addition with factors such as cigarette male individuals suffering from prostate cancer who smoking (Hanchette et al., 1992). About more than 60 worked in open air has been caught by the disease 3 to 5 observational studies based on exposition investigation years afterward in comparison with the men who were made in U.S proposes that insufficient vitamin D performed their jobs indoors (Ponsonby et al., 2002). levels may be allied with a privileged occurrence of Collective statistics from 970 women proved that the cancer in common (Ahonen et al., 2000; Li et al., 2007). maximum vitamin D intake is associated with a 50% lesser hazard of breast cancer in contrast with the lowest Some biological studies suggest that sunlight may shield (Van et al., 2004). Kids and young mature people who are from ovarian, colorectal, prostate and female breast exposed to the largest part of sunlight have a 40% cancers. A number of systematic researches also propose abridged risk of death from malignant melanoma once it a defensive concern between prostate plus colorectal develops and a lower risk of Hodgkin‟s lymphoma in cancer and circulating vitamin D (Wactawski et al., comparison with the people who slightly expose to 2006). Current epidemiological facts revealed a tough sunlight (Munger et al., 2006). correlation between meager vitamin D status and privileged risk for unending diseases of different etiology Anticancer actions of vitamin D (Lappe et al., 2007). Anticancer property of vitamin D has been deliberated in a large range of frequently encountering cancers (both in Deficiency of vitamin D and lack of sun exposure has vitro and in vivo) of which the actions on prostate, been found to cause unceasing illnesses together with colorectal and breast cancers have been considered to be various lethal cancers (Boscoe et al., 2006). It is now strong potentially (Chel et al., 1998). renowned that certain types of cancer as well as softening of bones , cardiovascular diseases and autoimmune Mechanism of action diseases can be avoided in case of retaining calcifediol The enzyme 1-OHase is used for changing of calcifediol concentration in serum of about 32ng/ml or a little into calcitriol and this has been experimentally greater. A theory was held up in the middle of 1970-2007 determined that calcitriol is synthesized by some tissues which was based on investigation of crucial and appraisal of the body involving colon, breast and prostate as they medical literature printed and suggested that calcitriol has possess the genes on them for the expression of enzyme a noteworthy shielding result against cancerous growth. 1-OHase, in addition to the synthesis of cacitriol from its Epidemiological investigations have shown an opposite predecessor in the kidney. link between serum concentration of calcifediol /sun exposure/ vitamin D intake and risk of developing and/ or At cellular level the mechanism of anticancer action of existing cancer. It seems to be effective to use vitamin D has not been entirely implicated. All normal supplements of vitamin D and levelheaded sun exposure cells along with cancerous cells possess on their surface and use of vitamin D supplements in avoidance of vitamin VDRs for conversion into calcitriol; the dynamic D insufficiency (Tuohimaa et al., 2007). Additionally it metabolite. These receptors fit in the super family of has also been found by many members of staff that were nuclear receptors, which comprise receptors for steroid/ searching on it that vitamin D is useful in bringing on thyroid hormone. A conformational change is occurred death of cancerous cells both in vitro and in vivo, except when the agonist calcitriol binds with VDR for its prevention (Feskanich et al., 2006). activation which in order dimerizes with the nuclear

An analysis has been made among the people living at retinoic X receptor. The binding of heterodimer with higher latitudes and lower latitudes as people with higher vitamin D response elements (VDREs) in the promoters latitudes have greater possibility for Hodgkin‟s lymphoma of objective genes and endorses their transcription People living at higher latitudes are at increased causing adjustments in differentiation, phosphocalcic possibility for Hodgkin‟s lymphoma in addition to metabolism or maintenance of cell division, and cell death ovarian, breast, colon, pancreatic, prostate and other (Ascherio et al., 2010). After binding with VDR, calcitriol cancers and are further expected to expire from these performs its function by regulating the function of over cancers, in comparison to lower latitudes (Chang et al., and above 60 genes providing direction for anti- 2206 Pak. J. Pharm. Sci., Vol.32, No.5, September 2019, pp.2203-2211 Muhammad Imran Qadir et al proliferative, pro-differentiating and anti-metastatic biological derangements exclusive to cancerous cells and outcomes on cells to effects anti-angiogenic property as to recognize new cellular targets for drugs used as the vitamin D is known to cause interference in the anticancer agents. A few of the drugs consist of - matrix transduction pathway of receptor tyrosine kinases metalloproteinase inhibitors to retard attack and put off (growth factor(s)-activated receptors) which modulates metastasis, antiangiogenic, which avert fresh development transcription thereby changing genomic functions of blood vessels that is crucial for cancer growth, providing disability of angiogenesis, apoptosis and cell inhibitors of signal transduction pathways to disrupt the differentiation (Aris et al., 2005). staid signaling pathways important for cellular enlargement and abundance, differentiation mediators to Management of cancer and vitamin D stay away the neoplastic cells in a phase where they The most important processes used of management and contain minute or rebuff proliferative prospective, cure of cancer comprise of surgical treatment, irradiation designer molecules, devised to restrain unbalanced and chemotherapy, generally provided in combination tyrosine kinase overexcited action and proapoptotic based on the form and phase of the illness. However in means which have straight deadly outcome for cancer most of cancers the intimate management is curative. cells or augment the cellular breaking actions of Because of the fact that untimely judgment is not anticancer agents (Dijkstra et al., 2004). achievable in common cases and the disease still continues untreatable in addition to all genuine and Chemoprevention reasonable techniques for treatment. Furthermore, the In view of the fact that several cancers at present are outcomes of radiation therapy and surgical procedures in untreatable, efforts may be done to check their incidence, conjunction with severe undesirable results of if achievable. In this case to minimize the risk of chemotherapy auxiliary bound the commencement and incidence of definite forms of cancer the way of living prolongation of treatment (Van et al., 2004). must be change most importantly. Likewise, chemoprophylaxis may be regarded for each and every The problem of resistance and tolerance to the existing inhabitant or for crowd of people having greater hazard drugs has created a decreased efficacy of these drugs. for a particular cancer. Ingestion of some vitamins and This problem has been tried to be overcome by the use of derivatives and dietary micronutrients like alpha- polymers (Khalid et al., 2009; Hussain et al., 2011; Irfan tocopherol, ascorbic acid, beta-carotene, isotretinoin and et al., 2016a; Irfan et al., 2016b; Qadir, 2017a) or through folic acid may restrain the growth of cancer. Big level nanotechnology (Naz et al., 2012; Ehsan et al., 2012), assessments in this deference are steps forward synthesis of new drugs, either by the use of proteomics (Wactawski et al., 2006). Because of their antitumor (Qadir, 2011), or synthesis from lactic acid activities, a few investigators suggest that vitamin D (Masood et al., 2011), or marine microorganisms (Javed supplementation may be valuable in the cure and et al., 2011). However, now-a-days, the trend is also anticipation of some categories of cancer (Zittermann, being changed to the use of natural products. Large 2006). numbers of natural constituents are constantly being screened for their possible pharmacological value Daily dose of vitamin D particularly for their analgesic (Hussain et al., 2017a & Presently, there are no recognized recommendations for b), anti-inflammatory (Qadir, 2009), hypotensive (Qadir, medicating vitamin D in the several patient inhabitants 2010; Qadir al., 2018), hepatoprotective (Ahmad et al., (teenagers, youngsters, adults and old age people, 2012; Qadir and Ahmad, 2017), hypoglycaemic (Qadir expecting women, or nourishing mothers). Nevertheless, and Ahmed, 2017) amoebicidal, anti-aging (Qadir and an estimation of lately issued literature advises that the Anwar, 2017), cytotoxic, antibiotic (Amin et al., 2012; presently indorsed daily stipends are perhaps too short Mannan al., 2016; Qadir al., 2016; Qadir and Sajjad, and that advanced doses are mandatory to attain the finest 2017; Qadir al., 2018), antibacterial (Qadir and results as a minimum in relations to colorectal cancer plus Chuahday, 2018; Qadir and Mobeen, 2018), spasmolytic, healthiness of bones. Youngsters with age 10-18 years bronchodilator, antioxidant (Janbaz et al., 2012), antiviral and elders greater than 60 years might have need of (Qadir and Abid, 2017; Qadir and Zafar, 2017; Qadir, advanced doses greater than 2,000 IUs/day. For new born 2018a) and anti-cancer properties (Qadir, 2016; Qadir, in the first initial year, require regular vitamin D3 dose of 2017b; Bashir and Qadir, 2017; Qadir and Cheema, 2017; approximately 2,000 IUs (Zhang et al., 2004). Qadir and Faheem, 2017; Qadir and Rizvi, 2017; Qadir, 2018b). Vitamin D may prove a strong candidate as anti- CONCLUSION cancer agent in near future. A person devoid of eating oily fish regularly, then it Recent approaches becomes very challenging to acquire that quantity of The quickly rising consideration of biological processes vitamin D3 from nutritional basis. Level headed sun which leads production of cancer has facilitated to utilize contact in addition to the use of supplements is required to Pak. J. Pharm. Sci., Vol.32, No.5, September 2019, pp.2203-2211 2207 Importance of vitamin D in cancer management justify the body‟s vitamin D prerequisite. 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