THE ROLE OF VITAMIN D IN REDUCING CANCER RISK AND PROGRESSION

Muhammad YounisSoutheast University, China.

Vitamin D3 Vitamin D3 is the precursor

to the potent steroid hormone calcitriol (1,25 dihydroxy vitamin D3 (1,25(OH)2D3)).

That regulates the expression of many genes in most tissues of the body.

Many studies in humans, but not all, suggest that higher intakes of vitamin D or higher levels of vitamin D in the blood are associated with a reduced risk of cancer. Vitamin D3

Vitamin D is a multifunctional pro-hormone

Dietary vitamin D3 is converted into 25 hydroxy vitamin D3 (25(OH)D3) in the liver; this is the circulating form of vitamin D, which is subsequently hydroxylated to form calcitriol by the cytochrome P450 enzyme CYP27B1 in the kidneys.

Calcitriol is also synthesized locally by CYP27B1 present in most extrarenal tissues, including many cancer cells, where it acts in a paracrine manner.

Levels of calcitriol are additionally regulated by the cytochrome P450 enzyme CYP24A1, which begins the inactivation of calcitriol through 24-hydroxylation.

Physiological Effects of Vitamin D

The Renal Endocrine Pathway And The Extrarenal Autocrine Or Paracrine Pathway Of Calcitriol Synthesis.

Calcitriol regulates multiple signalling pathways involved in proliferation, apoptosis, differentiation, inflammation, invasion, angiogenesis and metastasis.

Therefore has the potential to affect cancer development and growth.

Recent findings indicate that calcitriol also regulates microRNA expression and may affectcancer stem cell biology.

Multiple cell culture and animal models of cancer support a role for dietary vitamin D3 and calcitriol in retarding cancer development and progression; however, data from human clinical trials are thus far inconsistent.

Epidemiological studies suggest that vitamin D deficiency is associated with increased incidence of cancer and worse outcomes, although many studies do not demonstrate these associations.

Genomic Mechanism Of Calcitriol Action Through The VDR

vitamin D receptor (VDR), Retinoid X receptor (RXR)

Antineoplastic Action Of Vit: D

Calcitriol Regulation Of Specific Signalling Pathways That Drive Breast, Colon And Prostat Cancer Growth.

Vitamin D And Cancer Stem Cells

Calcitriol might have potent effects on the normal PSC population, and these cells might be the origin for prostate cancer when mutations convert them into CSCs.

Few studies have tested,reduction in cancer risk by calcitriol occurs by an effect on the CSC population of breast cancer.

In vitro and xenograft studies indicated that the calcitriol analogue BXL0124 decreasedtumour growth and reduced tumour CD44 levels.

Anti-proliferative Effect Interest in using vitamin D3 to reduce cancer risk,

further research is needed, particularly randomized controlled trials (RCTs), to demonstrate in humans whether individuals with low levels of circulating 25(OH)D are at increased risk of developing cancer and whether calcitriol or vitamin D supplements can reduce cancer risk and progression and improve outcomes.

Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) and vitamin D 3 synthesis and degradation pathways have been implicated in affecting the risk of cancer development.

Key Concepts And Findings From Animal Models Of Breast, Colon And Prostate Cancer

The inhibitory effects of calcitriol or vitamin D seem to be more effective chemoprevention setting early stages of cancer, rather than in the treatment of advanced, more aggressive cancers.

Calcitriol and vitamin D signalling in the various cancers is vitamin D receptor (VDR)-dependent, and loss of VDR leads to increased incidence, higher tumor burden and more aggressive phenotypes of cancer.

Key Concepts And Findings From Animal Models Of Breast, Colon And Prostate Cancer Dietary vitamin D deficiency by itself or with calcium

deficiency accelerates the incidence, growth and multiplicity of cancer and increases tumor burden that can be reduced by supplementation with vitamin D alone or combined with calcium.

Supplementation with dietary vitamin D slows the growth of tumours that continue to grow in rodents fed standard diets containing concentrations of vitamin D that are considered to be adequate for rodent bone health.

The reduction of tumour burden seems to be vitamin D dose-dependent.

Key Concepts And Findings From Animal Models Of Breast, Colon And Prostate Cancer Some calcitriol analogues might be more

effective in inhibiting tumour growth than calcitriol at equivalent doses, while exerting reduced calcaemic effects in rodent models.

Combinations of calcitriol with other anticancer drugs are more potent than the individual drugs in inhibiting tumor growth.

When calcitriol is combined with CYP24A1 inhibitors, anticancer actions, as well as hypercalcaemic effects,are increased.