The role of vitamin D in reducing cancer risk and progression

1. THE ROLE OF VITAMIN D IN
REDUCING CANCER RISK
AND PROGRESSION
Muhammad Younis
Southeast
University, China.

2. 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
Vitamin D3

3. 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.

4. Physiological Effects of
Vitamin D

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

6.  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
affect
cancer stem cell biology.

7.  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.

8. Genomic Mechanism Of
Calcitriol Action Through The
VDR
vitamin D receptor (VDR), Retinoid X receptor (RXR)

9. Antineoplastic Action Of Vit:
D

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

11. 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 decreased
tumour growth and reduced tumour CD44
levels.

12. 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.

13. 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.

14. 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.

15. 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.