1. By: Susan Albert

2. Vitamin K Fat soluble vitamin Stands between life and death Coenzyme Family of compounds Phylloquinone (K1) Menaquiones (K2) Menadione (K3) (Insel P., Turner, E., Ross, D., 2007)

3. Functions of Vitamin K Blood clotting Factor II, Factor VIII, Factor IX Inactive clotting factor X Vitamin K (adds carbon dioxide to glutamic acid) Calcium Factor Xa Prothrombin Thrombin (Gropper et al., 2009)

4. Bone Formation Inactive osteocalcin (substrate) Vitamin K Calcium Mechanism of action: carboxylation Active osteocalcin (product) (Insel et al., 2007)

5. Recommendations Deficiencies are extremely rare No tolerable upper intake level Adequate Intake (AI) Men: 120 micrograms/day Women: about 90 micrograms/day Children: 30-55 micrograms/day (Insel et al., 2007)

6. Sources of Vitamin K Other sources: vegetable oils (soybean, cottonseed, canola, and olive), animal products (egg yolks, butter, various cheeses, liver), soybean products (tofu) SourceGramsServingmcg Kale85~ ½ cup694 Spinach85~ 3 cups410 Turnip greens85~3 cups213 Broccoli85~ ½ cup120 Romaine lettuce85~ 1 ½ cups87 Beef liver853 oz3.3 (Insel et al., 2007)

7. Cancer Breast Colorectal Lung Liver (hepatocellular carcinoma) Pancreatic Prostate Factors that increase risk: tobacco, diet, exposure to carcinogens in environment/workplace (Insel et al., 2007)

8. Mechanism of Action Vitamin K-dependent carboxylation reactions Potential Anticancer agent (Ohlsson et al., 2004) Specific link to cancer is still unclear Number proposed Focus on oxidative capacity of K3 Cell line research K exerts inhibitory effects (Alternative Medicine Review, 2009)

9. Quick Review Sources of vitamin K? Functions? What are the three types?

10. What is the relationship between vitamin K and cancer?

11. Nimptsch, K., Rohrmann, S., Kaaks, R., & Linseisen, J. (2010). American Journal of Clinical Nutrition, 91(5), 1348-1358.

12. Overview Study Design Prospective cohort study 24,340 participants 11, 438 men & 12,902 women Enrollment until 2008 Objective Location of study

13. Method and Statistics Method Baseline Follow-up and outcome assessment Descriptive Mean Standard deviation Median Range Inferential Cox proportional hazards regression model with hazard ratios 95% confidence interval

14. Results Q1Q2Q3Q4P value K1 Cases/non-cases129/5956104/5982111/5975115/5969 HR*10.880.890.93 95% CI(0.68,1.14)(0.69,1.16)(0.71,1.22)0.70 K2 Cases/non-cases156/5928114/597290/599698/5986 HR*10.770.640.72 95% CI(0.60, 0.99)(0.49, 0.85)(0.53, 0.98)0.03 Cancer Mortality Note: adapted from Nimptsch et al., 2010 * Age and sex stratified

15. Results Q1Q2Q3Q4P value K1 HR*11.061.301.190.54 K2 HR*10.620.430.380.002 Lung Cancer Incidence Note: adapted from Nimptsch et al., 2010 * Age and sex stratified

16. Results Q1Q2Q3Q4P Value K1 HR*10.891.00 0.84 K2 HR*10.790.670.650.03 Prostate Cancer Incidence Note: adapted from Nimptsch et al., 2010 * Age and sex stratified

17. Other cancers Cancer typeP value for trend (K1) P value for trend (K2) Colorectal0.500.57 Premenopausal breast cancer 0.580.70 Postmenopausal breast cancer 0.510.57 Cancer Incidence Note: adapted from Nimptsch et al., 2010

18. Strengths and Weaknesses Strengths Hypothesis Large sample size Statistics Planning and organization Validity Weaknesses Validity

19. Conclusion No relationship between K1 and K2 Colorectal cancer incidence Pre & post menopausal breast cancer incidence No relationship between vitamin k1 Prostate cancer incidence Lung cancer incidence Cancer mortality Relationship between vitamin K2 Prostate cancer incidence Lung cancer incidence Cancer mortality

20. What is the relationship between vitamin K and cancer?

21. Sarin, S.K., Kumar, M., Hissar, S., Pandey, C., & Sharma, B.C. (2006). Journal of Gastroenterology & Hematology, 21(9), 1478-1482.

22. Overview Study Design: randomized controlled clinical trial Total participants: 42 Placebo group (n=19) High dose of vitamin K3 (n=23) Objective Location of study

23. Method & Statistics Method Baseline characteristics Criteria to be included (4) Treatment Descriptive statistics Median Range Mean Standard deviation Inferential statistics Student t-test Chi squared test Kaplan-Meier survival curves

24. Baseline Characteristics CharacteristicsVitamin K( n=23)Placebo (n=19)P-Value Age (years) Mean +/- SD50.7 +/- 11.951.7 +/- 8.40.859 Median4854 Range27-7241-69 Sex n (%) Male 18 (78.3) 15(78.9) 1.000 Female 5(21.7) 4(21.1) Etiology n (%) Hepatitis B 17(73.9) 15(78.9) 0.895 Hepatitis C 4 (17.4) 3(15.8) Other 2 (8.7) 1 (5.3) Note: adapted from Sarin et al., 2006

25. Results Groupn (%)Survival (months) median (range) 1-year survival n (%) High dose K3 Complete response1 (4.3)371/1 (100) Partial response3 (13)14 (11-28)2/3 (66.7) Objective response4 (17.4)21 (11-37)3/4 (75) Non-responsive19 (82.6)5 (1-16)4/19 (21.1) Stable disease4 (17.4)12.5 (3-16)3/4 (75) Progressive disease15 (65.2)3.5(1-13)1/14 (6.7) Placebo19 (100)5(1.5-21)3/19(15.8) Note: adapted from Sarin et al., 2006 Survival of patients with advanced heptacellular carcinoma treated with high dose K3 or placebo

26. Causes of death in patients with advanced hepatocellular carcinoma treated with high dose K3 or placebo TreatmentCancer related n (%) Hepatic failure n (%) Hemorrhage n (%) High dose K313 (56.5)6 (26.1)4 (17.4) Placebo14 (73.7)4 (21.1)1 (5.3) Note: adapted from Sarin et al., 2006

27. Kaplan-Meier survival curves

28. Strengths and Weaknesses Strengths Purpose Evidence of planning and organization Statistics clearly stated Population Weaknesses First trial for those with advanced liver cancer Demographics Population Small sample size

29. Conclusion More research is needed High doses do not affect overall survival Vitamin K3 does not cure cancer 1 patient achieved complete response 13% partial response 17.4% objective response All patients died

30. Final Conclusions The relationship between vitamin K and cancer

31. Vitamins A and D but not E and K decreased the cell number in human pancreatic cell lines B. Ohlsson, E. Albrechtsson & J. Axelson

32. Overview Study design Experimental Seven pancreatic cancer cell lines Objective Location

33. Method and Statistics Method Descriptive statistics Mean Standard deviation Inferential Statistics Kruskal-Wallis test Mann-Whitney U test

34. Results

35. Strengths and Weaknesses Strengths Purpose Evidence of planning and organization Statistics clearly stated Weaknesses Weaknesses Controlled environment Statistics Future research

36. Verdict Vitamin K1 No relationship Vitamin K2 Lung cancer incidence Prostate cancer incidence Overall cancer mortality Vitamin K3 More research needed

37. Future Direction American Cancer Society Vitamin K1 and K2 (Nimptsch et al., 2010) Biomarkers More studies in humans Vitamin K3 (Sarin et al., 2006). Larger studies Different dosages

38. Any questions?