Vitd and ovarian cancer


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vitd receptor and its down regulation of ovarian cancer

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Vitd and ovarian cancer

  1. 1. Vitamin D Receptor A Novel Drug Target forOvarian Cancer Treatment Presented by: Eswara chandra murahari Department of Pharmacology Reg no:1228310106 GITAM Institute of Pharmacy 1
  2. 2. Ovarian cancer• Ovarian cancer is the leading cause of the gynecological cancer mortality . Globally it accounts for 10% total deaths of women every year and thousands of new cases were diagnosed each year.• Cancerous growth arising from the ovary• Most (more than 80%) ovarian cancers are classified as "epithelial" and are believed to arise from the surface (epithelium) of the ovary and remaining are• Specialized gonadal stroma• Choriocarcinoma• Teratoma 20%• Brennets tumour 2
  3. 3. Signs and symptoms of ovarian cancer• The symptoms persist for several months before being recognized and diagnosed.Symptoms such as :• Abdominal pain or discomfort,• bloating, back pain,• Urinary urgency,• Constipation,• Tiredness and a range of other non-specific symptoms.Specific symptoms• Pelvic pain,• Abnormal vaginal bleeding or involuntary weight loss,• There can be a build-up of fluid (ascites) in the abdominal cavity. 3
  4. 4. Causes and Risk factors• The exact cause of ovarian cancer remains unknown. The risk of developing ovarian cancer appears to be affected by several factors.• Older women, and in those who have a• Hereditary forms of ovarian cancer can be caused by mutations in specific genes most notably p53 ,BRCA1 and BRCA2.• Infertile women• Those with a condition called Endometriosis.• Those who have never been pregnant.• Those who use postmenopausal estrogen replacement therapy are at increased risk.• Analysis of 489 high-grade serous ovarian adenocarcinomas found that the p53 gene was mutated in 96% of cases. Other genes commonly mutated were NF1, BRCA1, BRCA2, RB1 and CYCLIN DEPENDENT KINASE 12 (CDK122). 4
  5. 5. Therapies• Antiangiogenesis (angiostatin,endostatin)• Antisense therapy (directing the keyoncogens)• Apoptosis promoters (optosis in selective cells)• Cell cycle inhibitars ( inhibits key steps in cell cycle)• Gene therapy (replacing mutated genes)• Farnesyl transferase inhibitors (inhibits ras protein)• Glycosylation inhibitors (alters pattern of surface glycoproteins)• Monoclonal antibodies (against oncogene encoded receptars)• Protien kinase inhiitors (essential proteins in tumour cells)• Ribosymes (degrade RNA moecules uique to cancer cells)• Telomerase inhibitors (active enzyme in tumour cells)• Vaccines (boost T-cell immune response) 5
  6. 6. Y novel drug is needed?• Poor outcome of the treatment.AMERICAN CANCER SOCIETY:30,000 new cases of ovarian cancers diagnosed every year.In this 70% die from this diseaseOne in every 68 women are dying due to ovarian cancer.• From 1930 the death mortality rate has raisen up to 250%(annual report).MAIN REASONS:• Poor prognosis due to no reliable diagnosis method.• Symptoms seen only after the disease spreads ,following 5y survival period. 6
  7. 7. Vitamin-D(“sun” medicine) 7
  8. 8. Vit-d insufficiency & ovarian cancer• Data compiled by water house etal OCMR is lowest in countries with in 20 degrees of the equator( high amt of sun light). Women living in north sideof any country has 5 times highermortality rate than women in south. This shows a correlation b/w decreased Sunlightand ovarian cancer. 8
  9. 9. Vitamin-D receptor(VDR-NR1I1)• Ligand regulated transcription factor• Super family: steroid/thyroid hormone receptor/nuclear receptorSteroids non steroids orphan nuclear receptorsProgesterone Thyroid fatty acidsAndrogen Trans retinoic acid steroidsEstrogens Retinoid x receptor bile acidsGlucocorticoids Vitamin-D xeno-bioticsmineralocorticoids 9
  10. 10. Receptor structure• Made of 427 amino acids• A/B region made of 21 residuesAF2-activation center(AF1 is absent)Amino terminal region• C region:22-114 residuesDNA binding domainZinc finger motifs• D region:115-166 residuesHinge region(for flexibility)• E region:167-427 residuesLigand binding domainCarboxy terminal group 10
  11. 11. Heterodimerization• Normally steroid receptors undergo homodimerization• But ,non steroids undergo heterodimerisation with Retinoid X Receptor(RXR)• RXR-VDR is the functional form that mediates 1α25(0H)2D3• Transcriptional activatorsCSRC,DRIP,SMRT,NCOR,SWFHistone remodification-transcriptionRegulation• Histone deacetylates 11
  12. 12. Molecular mechanism of 1α25(0H)2D3 action in ovarian cells• Immunochemistry in rats and ligand based assays in hens showed that ovary is the target organ for 1α25(0H)2D3.• growth analysis studies demonstrated a decrease in cell number by 1,25(OH)2D3 in both Chinese hamster ovary and OVACAR3 cells.• 1,25(OH)2D3 suppresses the growth-stimulatory effect of dihydrotestosterone (DHT) in OVCAR3 cells.• Immunoblotting analysis also reveals that the expression of the AR is upregulated by 1,25(OH)2D3.• Growth suppression could be due to either decreased rate of proliferation or increased rate of cell death.• Flow cytometry analyses showed that treatment of OVCAR3 cells with 1,25(OH)2D3 caused a decreased in the percentage of cells in S phase. 12
  13. 13. • These findings show that the blockage of OVCAR3 cells at both G1/S and G2/M checkpoints contributes to the decreased rate of proliferation induced by 1,25(OH)2D3• longer treatment with1,25(OH)2D3 induced apoptosis in OVCAR3 cells.• suggesting that the active vitamin D compound exerted a long-lasting effect on ovarian cancer growth. 13
  14. 14. 1,25(OH)2D3 Induces Cell Cycle Arrest of Ovarian Cancer Cells at G1/S Checkpoint by Increasing the Protein Stability of P27Kip1• Eukaryotic cell cycle is driven by a family of serine/threonine protein kinases, namely the cyclin-dependent kinase (CDK).• To the opposite, CDK inhibitors such as p27kip1 and p21Cip1 are molecules that negatively regulate cell cycle progression by binding to and suppressing cyclin-CDK activities.CDK4/6-RB-E2F AXIS: 14
  15. 15. CDK Cyclin-D Phosphorylate retiniblastoma Cyclin-A RB E2F Cyclin-E p27kip1 Cyclin-E Cdk2 complex phosphorylationGrowth inhibitory signals p27kip1 Skp2 E3 ligase Proteosomal degradation p27kip1 complex 15 ubiquitination
  16. 16. G2/M Arrest by 1,25(OH)2D3 in Ovarian Cancer Cells Mediated through the Transcriptional Induction of GADD45• GADD45(Growth Arrest and DNA Damage) is a small acidic globular protein that was identified as one of the grow arrest and DNA damage inducible genes.(it has essential role in DNA repair and Genomic stability).• It is transcriptionally up-regulated by p53 and BRCA1 tumor suppressors and a variety of genotoxic and non-genotoxic stress signals. 16
  17. 17. 1α25(0H)2D3 VDR-RXR complex VDR-RXR complex Promotor gene for GADD45 Poly II complex Disturbed cell cycle progression in M-phase Decrease in Regulate CDC2 levels of Cyclin-B kinase 17
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  19. 19. Induction of Ovarian Cancer Cell Apoptosis by 1,25(OH)2D 3 through the Down Regulation of Telomerase• Normal cell:Short telomeres leads to irrevesible growth arrest or senescence• Cancer cell:Telomere length is maintainedby telomerase enzyme• Telomerase:Telomerase associated proteinsand Telomerase RNAReverse transcriptionTelomeric DNA repeats 19
  20. 20. 20
  21. 21. Summary 21
  22. 22. Conclusion and Perspective• The hormone achieves these regulations through diverse mechanisms with clearly distinct outcomes.• The overall effect is decreased rate of cell growth in vitro and suppression of ovarian tumors in animals.• The studies clearly suggest that the suppressing effects of 1,25(OH)2D3 on ovarian cancer cell growth are mediated through its genomic action in nucleus.• Available synthetic 1,25(OH)2D3 analogs such as EB1089 as chemotherapeutic agents for ovarian cancer patients.• Many vitamin D analogs with more potent anti-tumor activity and less calcemic side effect had been successfully developed.• vitamin D and its receptors is expected to lead to the development of more potent and safer vitamin D analogs that can eventually be applied clinically to treat patients with ovarian cancer. 22
  23. 23. References1. Xiaohui Zhang, Santo V. Nicosia and Wenlong Bai* Vitamin D Receptor is a Novel Drug Target for Ovarian Cancer Treatment, Current Cancer Drug Targets, 2006, 6, 229-244 2292. Heintz, A. P.; Odicino, F.; Maisonneuve, P.; Beller, U.; Benedet, J.L.; Creasman, W. T.; Ngan, H. Y.; Pecorelli, S. Carcinoma of the ovary. Int. J. Gynaecol. Obstet. 2003, 83(Suppl. 1), 135-166.3. Stokstad, E. The vitamin D deficit. Science 2003, 302, 1886-1888.4. MacLaughlin, J. A.; Anderson, R. R.; Holick, M. F. Spectral character of sunlight modulates photosynthesis of previtamin D3 and its photoisomers in human skin. Science 1982, 216, 1001- 1003.5. Blutt, S. E.; Polek, T. C.; Stewart, L. V.; Kattan, M. W.; Weigel, N. L. A calcitriol analogue, EB1089, inhibits the growth of LNCaP tumors in nude mice. Cancer Res. 2000, 60, 779- 782.6. Chen, J. D.; Evans, R. M. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 1995, 377, 454- 457.7. JoEllen Welsh, Jennifer A. Wietzke, Glendon M. Zinser, Belinda Byrne,Kelly Smith and Carmen J. Narvaez,Vitamin D-3 Receptor as a Target for Breast Cancer PreventionDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 23
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