vitamin D as a anticancer agent

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Introduction :

Introduction Vitamin –D or calcitriol is a steroid hormone Its active form is 1-25 dihydroxycholecalceferaol Essential for formation, growth, and repair of bones and for normal calcium absorption Obtained from exposure of the skin to ultraviolet radiation in sunlight & from some foods and dietary supplements

Synthesis of vitamin D:

Synthesis of vitamin D


Functions Vitamin D It helps maintain adequate blood levels of the calcium and phosphate for bone formation, mineralization growth & repair, improve muscle strength and immune function It promotes the absorption of calcium from the small intestine, reabsorbtion from kidney It helps reduce inflammation It helps in cancer protection

Vitamin D and cancer :

Vitamin D and cancer

History :

History In 1919 Sir Edward Mellan was working indoors with dogs and horses during the winter and concluded that if they didn´t get sunlight they developed bone disorders In the 1930´s by Professor A Windaus of the University of Gottingen, Germany revelled its chemical structure and thus vitamin D came about Similarly, in 1936 Peller analyzed the relationship between morbidity and mortality of cancer and exposure to radiation In 1941, Apperley analyzed the incidence and mortality rate of cancer with respect to sun exposure

What is cancer :

What is cancer Cancer (malignant neoplasm ) is a class of a disease in which a group of cell display uncontrolled growth (division beyond the limits) invasion (intrusion on and destruction of adjacent tissues) and sometime metastasis(spread to other parts of body via. Lymph or blood)

Role of vitamin D:

Role of vitamin D The non-calcium mobilizing functions of vitamin D associated with cancer are :- Cell proliferation & Differentiation Apoptosis Angiogenesis

Cell proliferation, differentiation and tumor growth:

Cell proliferation, differentiation and tumor growth

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For proliferation, the cell passes through several stages of cell cycle These are G0-G1-S-G2-M Of which S (phase of DNA synthesis) and M (phase of mitosis) These are two check points in the cycle

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On stimulus G 0 phase is recruited into the G 1 phase and the cycle continues Stimulus is growth factor and cytokines Stimulus act on the cell surface receptors i.e receptor tyrosine kinases (RTKs) Ligand binding to RTK cause signal transduction cascade leading to formation of cell cycle regulators controlling cell proliferation, differentiation and division

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Signal transduction system involves Ras/ Raf pathway (Ras is a proto- oncogenic product and Raf is a serine/ threonine kinase) which activates the kinase cascade by sequential phosphorylation of the kinases leading to gene expression resulting in the progression of the cell cycle and ultimate cell division Two positive regulators are – cyclins and cyclin dependent kinases(CDKs) Negative regulatory protein – the retinoblastoma (Rb) protein , cdk inhibitory protein (CIP) family, comprising of proteins p21, p27 and p57 and the inhibitors of kinases ( InK family) having proteins p16, p19, and p15

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Decrease in cyclin-D Rb is hypophosphorylated This bound to transcription factor E2F & prevents its (E2F) controlling function on gene expression that code for cyclins E and A, DNA polymerase, thymidine kinase, dihydrofolate reductase, etc. - thereby holding the cell cycle in check at check point 1 Growth factor action increases the concentration of cyclin D via Ras/ Raf kinase cascade activation and cyclin D/ cdk 4 and 6 complex cause phosphorylation of the Rb proteins – cell division

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Cytokine /GF TKR grb2 Ras Raf MAP ERK1/2 G0 Proto oncogenic Mitogen activated protein Extracellular signal regulated kinase 1&2 Cyclin D /CDK4 Cell proliferation

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GF /Cytokine Increase in cyclin D Rb Rb E2F E2F Phosphorylation of Rb Transcription Transcription Activate gene for synthesis of compound required for DNA synthesis during S phase

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The p53 gene codes the transcription factor p53 protein( +nt in low concentrations in healthy cells) DNA damage increases its concentration, which in turn activates the transcription of several other genes including the one, which codes for the protein p21 p21 causes inactivation of cyclin / cdk complexes Thereby preventing Rb phosphorylation and inhibition of cell cycle progression through G 1 phase resulting in arrest of cell cycle at check point 1

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As the cycle does not progress, the damaged DNA gets adequate time for its repair by the DNA repair system If successful the cycle overcomes the blockade at check point 1 and enters into S phase Failure of DNA repair leads to apoptosis

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DNA damage Increase P53 p21 Prevent Rb phosphorylation Inactivation of cyclin /CDK complex Repair Not repair Inhibition of cell cycle at s phase Apoptosis DNA Time for repair

Role of vitamin D :

Role of vitamin D In several cancer cells including breast cancer cell lines, calcitriol has been found to cause dephosphorylation of the Rb gene product, leading to blockade of cell cycle at check point 1 and hence tumor growth inhibition Calcitriol inhibits Src tyrosine kinase in Ras/ Raf kinase cascade, thereby leading to subsequent decrease in activity of ERK 1/ 2 and MAP kinase, this in turn reduces the formation of cyclin/ cdk proteins thus inhibition of cell proliferation

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Attempts have been made to amplify negative regulation thereby bringing a halt to the unrestricted proliferation of cancer cells Vitamin D has been found to inhibit cancer cell proliferation by increasing the activity of the CDKIs p21 WAF 1/ Cip 1 and p27 Kip Audo et al . have observed vitamin D to induce cell cycle arrest at G 1 phase which may be due to up regulation of CDKIs Audo et al . found a VDRE to be present in the promoter of p21 gene, which indicates that vitamin D may directly activate the transcription of p21

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Researchers have also shown that in high-grade carcinomas, VDR is down regulated, which may be due to alteration in the activity of p53 A study conducted by Dr. S. Chistakos reported that calcitriol has been found to induce a tumor suppressing protein (cystatin D) that can also inhibit the growth of breast cancer cells

Apoptosis and tumor growth :

Apoptosis and tumor growth

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Apoptosis :- Apoptosis is a genetically programmed well-organized built-in self-destruct mechanism, where sequence of biochemical events lead to cell death and its removal without inducing inflammatory reactions as occurs in necrosis

Pathophysiology of apoptosis :

Pathophysiology of apoptosis The process of apoptosis is effected by caspases, which are present in the cell in inactive non-functional form Apoptotic initiating factor (AIF) is a protein which after getting released from mitochondria enters the nucleus and switches on the process of apoptosis There are two pathways for caspase-mediated apoptosis Death receptor pathway and the other is mitochondrial pathway

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The mitochondrial pathway is activated when there is DNA damage DNA repair after its damage is mediated mainly by p21 proteins (mentioned earlier) If such repair does not occur p21 protein becomes proapoptotic along with another proapoptotic protein Bcl-2 (Bcl-2 associated X protein or BAX) coded by p53

Vitamin-D & Apoptosis :

Vitamin-D & Apoptosis Audo et al . found vitamin D analogues attenuate retinoblastoma tumor growth in athymic mice by increasing apoptosis which was associated with up regulation of both p53 and p21 vitamin D to cell lines of glioma and carcinoma breast and found it (vitamin D) to induce apoptosis in both of them In glioma cell lines, there was upregulation of BAX (proapoptotic) with down regulation of antiapoptotic Bcl-2, which indicated that vitamin D-induced apoptosis was mediated through p53 pathway Calcitriol has been found to decrease Bcl-2 expression in breast cancer cell lines

Angiogenesis and tumor growth:

Angiogenesis and tumor growth

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Angiogenesis :- It refers to the growth of blood vessels from pre-existing vasculature

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Factors responsible for angiogenesis :- Growth factors Matrix metalloproteinase Interleukin -8 Vitamin D binding protein

Pathophysiology of angiogenesis :

Pathophysiology of angiogenesis Tumours (both primary and metastatic) do not grow beyond 2-3 and cannot metastasize unless adequately vascularised Process of tumor angiogenesis begins when the angiogenic switch Which gets ‘on’ due to a tilting of the balance between pro- and anti- angiogenic factors in favour of angiogenesis

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The process begins with the activation of ECs by growth factors followed by their proliferation and migration through the degraded extracellular matrix (by proteases) into the tumor This resulting in sprouting and finally formation of new capillary tubes

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Hypoxia causes transcriptional induction of the gene encoding VEGF whose receptors (VEGFR 1 , VEGFR 2 and VEGFR 3 ) belong to the family of RTKs VEGF-induced angiogenesis is mediated through VEGFR 2 Ligands for RTKs are angiopoietins(Ang1 and Ang2) Ang1 imparts quiescence and stability to the mature blood vessel via Ang1/ Tie2 pathway and hence antagonizes tumor angiogenesis Ang2 destabilizes the vasculature and thereby makes the host ECs more sensitive to the angiogenic signals coming from tumor cell-derived VEGF Thus Ang2 favors tumor angiogenesis.

Vitamin D & GF:

Vitamin D & GF Calcitriol has been found to interfere with EC activation, proliferation, migration, sprouting and tube formation with participation of intracellular signaling pathways Calcitriol inhibit the growth of tumor derived endothelial cells (TDECs) Calcitriol increase the number of VDRs and the level of apoptogenic protein p27 in TDECs thereby making them more vulnerable to its antiangiogenic and apoptotic action

Matrix metalloproteinase :

Matrix metalloproteinase Matrix metalloproteinases secreted by stromal cells and tumor associated macrophages, play an important role in tissue remodelling & on cell behaviour like proliferation, migration, differentiation, angiogenesis, apoptosis and host defence MMPs cause degradation of extracellular matrix (ECM) and disruption of capillary basement membrane which is essential for EC migration and invasion

Interleukin -8:

Interleukin -8 Interleukin-8 secreted by several cells including the tumor cells interacts with its receptors CXC- chemokine receptors 1 and 2 (CXCR1 and CXCR2) expressed on both normal and tumor cells Bao et al . found that IL 8 play role in angiogenesis and calcitriol found to inhibit IL-8 formation at nuclear level

Vitamin D-binding protein :

Vitamin D-binding protein It a transporter of vitamin D in the plasma It is also the precursor for the principal macrophage activating factor (maf) and is converted to DBP-maf Macrophages possess phagocytic action ,which is exerted on ECs and tumor cells leading to there destruction & hence inhibition of angiogenesis

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It has also been shown complex inhibit tumor growth in vivo , which is thought to be due to its antiangiogenic action Tube formation assay, conducted by Fannon shown a synergistic inhibitory action on endothelial tube formation when vitamin D was administered with DBP- maf

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Vitamin D not only has got preventive effect on cancers but also is capable of causing their regression and death of the constitutive cancerous cells up to various degrees The mechanism involved in such anticancer actions include its antiproliferative, prodifferentiating, apoptotic and antiangiogenic properties

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All these anticancer actions of vitamin D have been found with chronic administration of high doses, ranging between 2000-4000 IU/ day, which may lead to vitamin D toxicity Some workers have demonstrated the anticancer action with a dose of 1000 IU/ day without any adverse effect

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In this respect to avoid the high dose sunlight (UV radiation) exposure for a certain time period daily has been recommended which is thought to supplement and make up the dose deficit without toxicity Compound is not suitable for use in cancer as a primary anticancer agent It may be used as an adjuvant in combination chemotherapy

Studies favoring the facts :

Studies favoring the facts St. George´s Hospital Medical School in London and US researchers at Harvard and University of California showed that women with the highest levels of vitamin D were up to 50 per cent less likely to develop breast cancer The Journal of Steroid Biochemistry and Molecular Biology reviewed two studies concluding that women with the highest blood levels had the lowest risk of breast cancer One study showed that the lower blood levels of vitamin D, the more dense (and dangerous) the breast tissue

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In the Journal of Clinical Oncology (Jan 20, 2005) men with the highest levels of vitamin D in their blood were half as likely to develop prostate cancer St George’s Hospital showed that the provision of 400IU’s of vitamin D reduced pancreatic cancer by 34 per cent Hollick cleared that vitamin D reduces the risk of breast, colon, prostate and ovarian cancers

Take home message :

Take home message Recommended daily intake is :- 1–70 years of age: 600 IU/day (15 μg/day) 71+ years of age: 800 IU/day (20 μg/day) Pregnant/lactating: 600 IU/day (15 μg/day) Vitamin D is believed to have a role in controlling genes linked to major diseases such as certain types of cancers, dementia, and autoimmune disorders Anybody with cancer, or at high risk of developing it, will do themselves no harm with a daily dose of up to 10,000 IU

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Vitamin D can adjust almost everything in the cancer cell, from its genetic messaging to its cytoskeleton It can switch genes on and off, and it can reduce cell division, and it can ‘calm’ the cancer cells so that they settle rather than spread

References :

References Chakraborti CK . Vitamin D as a promising anticancer agent .ijp 2011;43:113-20. www.cancer active .com

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Are you getting enough vitamin D ????

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