What is the Relationship Between Vitamin K and Cancer?

What is the Relationship Between Vitamin K and Cancer?By: Susan Albert

1Vitamin K Fat soluble vitaminStands between life and death CoenzymeFamily of compoundsPhylloquinone (K1)Menaquiones (K2)Menadione (K3)

(Insel P., Turner, E., Ross, D., 2007) Cofactor: for posttranslational y-carboxylation of VK dependent proteins Phylloquinones: the form of vitamin K that comes from plant sources, major form in diet and most biologically active. Menaquiones: Forms of Vitamin K that come from animal sources. Also produced by intestinal bacteria Menadione: synthetic substance (synkayvite and hykione A medical form of vitamin k that can be toxic to infants 2Functions 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)Blood clotting: series of reactions forms a clot that stops the flow of blood. This cascade reaction involves the production of a series of proteins (fibrin). Four of the procoagulation proteins in the cascade are vitamin K dependent. Require calcium for activation. Then Prothrombin to Thrombin

3Bone Formation

Inactive osteocalcin (substrate)

Vitamin K CalciumMechanism of action: carboxylation Active osteocalcin (product)

(Insel et al., 2007)Vitamin K is thought to work by facilitating a process needed to allow the protein osteocalcin to strengthen the skeleton. Important for carboxylation of osteocalcin which allows it to become saturated with carboxyl groups. 4Recommendations Deficiencies are extremely rareNo tolerable upper intake level Adequate Intake (AI) Men: 120 micrograms/dayWomen: about 90 micrograms/dayChildren: 30-55 micrograms/day

(Insel et al., 2007)Adults younger than 45 consume about 60 to 110 mcg of K1/dayAdults over 55 range from 80 to 210 mcg /day of K1 400 mcg a day to support role in bone healthVitamin K overdose seen in newborns who receive vitamin K3 rather than K15Sources of Vitamin K Other sources: vegetable oils (soybean, cottonseed, canola, and olive), animal products (egg yolks, butter, various cheeses, liver), soybean products (tofu) SourceGramsServingmcgKale85 ~ cup694Spinach85~ 3 cups410Turnip greens85~3 cups213Broccoli85~ cup120Romaine lettuce 85~ 1 cups87Beef liver 853 oz

3.3(Insel et al., 2007)Oils: not reliable source, when exposed to light in transparent bottles, light degrades Vitamin KAnimal products contain lower amount of vitamin K Mcg: microgramsVitamin K is also found living in our intestine, absorbed in the small intestine and Vit K produced by bacteria is absorbed in the intestine

6Cancer BreastColorectalLungLiver (hepatocellular carcinoma) Pancreatic ProstateFactors that increase risk: tobacco, diet, exposure to carcinogens in environment/workplace

(Insel et al., 2007)Cancer: A term of disease in which abnormal cells divide without control. Cancer cells can invade nearby tissues and spread throughout the blood stream and lympathic system and other parts of the body. There have been studies done relating to all of these types of cancers. I will using the research I have found to show you the connection between Vitamin k and these types of cancers

Cancer2nd leading cause of death in the US and CanadaOne in every 4 deaths in the nation are from cancerGroup of more than 100 disease uncontrolled division of the bodys cellsNormally: the body only reproduces cells when there is a need Three phases of developmentInitiation: occurs when something alters a cells genetic structure and prepares it to act abnormally during later stagesPromotion: a reversible stage, occurs when a chemical or other factor encourages initiated cells to become activeProgression: occurs when promoted cells multiply and perhaps invade surrounding healthy tissueFactors that increase risk: tobacco, what we eat and drink, exposure to UV light, and exposure to carcinogens (cancer causing agents) in the environment and the workplace (Insel et al., 2007)

7Mechanism of Action Vitamin K-dependent carboxylation reactions Potential Anticancer agent (Ohlsson et al., 2004)Specific link to cancer is still unclear Number proposedFocus on oxidative capacity of K3 Cell line researchK exerts inhibitory effects(Alternative Medicine Review, 2009)Cell line research: various results have shown inhibitory effects 8Quick ReviewSources of vitamin K?Functions?What are the three types?

9What is the relationship between vitamin K and cancer?10Dietary vitamin K in relation to cancer incidence and mortality: Results from Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg) Nimptsch, K., Rohrmann, S., Kaaks, R., & Linseisen, J. (2010). American Journal of Clinical Nutrition, 91(5), 1348-1358.

11OverviewStudy DesignProspective cohort study24,340 participants 11, 438 men & 12,902 women Enrollment until 2008 ObjectiveLocation of study

Prospective cohort study: outcome is unknown at the beginning of the study. Large number of people followed over a period of timeIn this study: 24, 340 aged 35-64 from enrollment (1994-1998) until 2008, incidence of cancer as well as mortality was reported 11, 438 men and 12, 902 women. excluded: men who ate less than 888 kcals/more than 5585 kcals women who ate less than 705 kcals/more than 4316 kcals those with cancer except those with nonmelanoma skin cancer n=955 Objective: To see if there is connection between vitamin K1 and K2 intake with overall cancer incidence as well as mortality, previous studies have showed that intake of K1 and K2 inhibit growth in various cancer cell lines. 17 different types of cancer reported results will be presented for lung cancer (128 cases), breast (361 cancers), prostate (328 cases) and colorectal (180 cases) rest were below 100 Location: Heidelberg, south-west Germany 12Method and StatisticsMethodBaseline Follow-up and outcome assessment DescriptiveMeanStandard deviation MedianRange

InferentialCox proportional hazards regression model with hazard ratios95% confidence interval

Methods:Baseline: Dietary intake during 12 months after enrollment using food frequency questionnaire made up of 148 food and beverages items, asked typical portion size. Information also collected on lifestyle factors, smoking, physical activity, personal interview vit K intake was calculated by using HPLC-based food-composition data K1 (UK database) K2: dutch publication Average daily intake was calculated by multiplying the portion size, daily frequency of intake, content of K1 and K2 in each food item Follow-up: follow-up questionnaires mailed to participants at regular time intervals. Greater than 91.5 response rate Cancer cases: verified, medical records, death certificates reviewed up until August 2008 Results collected until diagnosis or death 13Results Q1Q2Q3Q4P valueK1Cases/non-cases129/5956104/5982111/5975115/5969HR*10.880.890.9395% CI(0.68,1.14)(0.69,1.16)(0.71,1.22)0.70 K2Cases/non-cases156/5928114/597290/599698/5986HR*10.770.640.7295% 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 stratifiedQuartiles: sex specific, ranges less than 26 mcg, 26 to less than 35 mcg, 35 to less than 46, more than 46 for men Women: less than 23, 23 to 32, 32 to 42, 42 and up mcg p value= 0.05

K1 led to no overall cancer reduction in all cancer cases Stronger relationship found between K2 and prostate cancer in men as well as lung cancer

Age and sex stratified for alcohol intake, BMI, waits to hip ratio, smoking, physical activity and education levels 14Results Q1Q2Q3Q4P valueK1HR*11.061.301.190.54K2HR*10.620.430.380.002Lung Cancer IncidenceNote: adapted from Nimptsch et al., 2010* Age and sex stratifiedHazard ratiosBelow protective all K2, p value significant for K2 15Results Q1Q2Q3Q4P ValueK1HR*10.891.001.000.84K2HR*10.790.670.650.03Prostate Cancer Incidence Note: adapted from Nimptsch et al., 2010* Age and sex stratifiedAll protective for K2, stat significant 16Other cancersCancer typeP value for trend (K1)P value for trend (K2)Colorectal0.500.57Premenopausal breast cancer 0.580.70Postmenopausal breast cancer0.510.57 Cancer Incidence Note: adapted from Nimptsch et al., 2010P for trend: across all quartiles all above 0.05 17Strengths and Weaknesses StrengthsHypothesisLarge sample sizeStatistics Planning and organizationValidityWeaknessesValidityStrengths Hypothesis: clearly stated, hypothesized that dietary intake of K1 and K2 may be associated with overall cancer incidence and mortality, presented the association of most frequent diagnosed cancers (lung, colorectrum, breast, and prostate. Wide range of cancers studied. Large sample size: 24, 340 participants, ages 34-65 more numbers= more statistical power Statistics: clearly stated, specific percentages, means, SD, dietary intake, etc five different tables to break down information by quartile and sex Planning and organization: could be repeated based off the description presented in the design section, how many participants used, the age range, free of cancer at beginning, program used (HPLC-based food comp data. Inferential stats used to determine final results. Validity: validated FFQ meaning there was a comparison between the baseline and the FFQ Validity: collection of data through FFQ to estimate individual intake of vitamin K. Could have caused an internal distortion of the results through subject bias, researchers looking for certain answers. 18ConclusionNo relationship between K1 and K2 Colorectal cancer incidence Pre & post menopausal breast cancer incidence

No relationship between vitamin k1 Prostate cancer incidenceLung cancer incidence Cancer mortality

Relationship between vitamin K2 Prostate cancer incidenceLung cancer incidence Cancer mortality

19What is the relationship between vitamin K and cancer?20High dose vitamin K3 infusion in advanced hepatocellular carcinomaSarin, S.K., Kumar, M., Hissar, S., Pandey, C., & Sharma, B.C. (2006). Journal of Gastroenterology & Hematology, 21(9), 1478-1482.

21OverviewStudy Design: randomized controlled clinical trialTotal participants: 42Placebo group (n=19)High dose of vitamin K3 (n=23) ObjectiveLocation of study

Study design: Research study in which patients are randomly assigned to a control group (receiving the standard treatment) or an intervention group. Control group was the placebo group (19), intervention group (n=23). Study was made up of 42 patients with advanced liver cancer stage C with portal vein thrombosis (blood clotting occurring in the wrong place, affects the hepatic portal vein and can lead to hypertension and reduction in blood supply to the liver.)

Location: New Delhi, India, GB Pant Hospital 22Method & Statistics MethodBaseline characteristicsCriteria to be included (4)Treatment

Descriptive statistics MedianRangeMeanStandard deviation

Inferential statisticsStudent t-testChi squared test Kaplan-Meier survival curves

Baseline: age, sex, etiology (where disease originated from hep B, C or other at the beginning of the studyCriteria: 1) advanced liver cancer, 2) unresectable cancer (surgery cant remove tumor), 3) no treatment within the last 6 months (active treatment, surgery, radiotherapy, chemotherapy 4) Cancer has spread to surrounding tissues indicated by MRI and CT People with end stage were not included. Enrolled between 2001 and 2004, performed in 2005

Treatment: given either placebo or high dose K3 through a IV of 50 mg/day with a daily increase of 50 mg/day for 6 days. Intramuscular 20 mg twice a day for 2 weeks. Treatment was continued until withdrawal or death after the progression of the disease.

23Baseline Characteristics

CharacteristicsVitamin K( n=23)Placebo (n=19)P-ValueAge (years) Mean +/- SD50.7 +/- 11.951.7 +/- 8.40.859 Median4854 Range27-7241-69Sex n (%) Male18 (78.3) 15(78.9)1.000 Female5(21.7)4(21.1)Etiology n (%) Hepatitis B17(73.9)15(78.9)0.895 Hepatitis C4 (17.4)3(15.8) Other2 (8.7)1 (5.3) Note: adapted from Sarin et al., 2006 24Results 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 Complete response: disappearance of all measureable lesions in the liverPartial response: reduction in tumor size by 50%Objective response: complete + partial responseProgressive: less than greater than 25% increase in any lesion Stable disease: not meeting any of the other definitions 25Causes 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 26 Kaplan-Meier survival curves

27Strengths and WeaknessesStrengths Purpose Evidence of planning and organization Statistics clearly stated Population

Weaknesses First trial for those with advanced liver cancer Demographics Population Small sample size

Purpose: the aim of the present study was to assess the clinical efficacy of high dose K3 in the treatment of patients with advanced liver cancer Evidence: Experiment could be completed again Stats clearly stated through 3 tables Population: large age range, both males and females

Demographics: all from India Population: All are in stage three liver cancer Sample size: 42 28Conclusion More research is needed High doses do not affect overall survival Vitamin K3 does not cure cancer 1 patient achieved complete response 13% partial response17.4% objective response All patients died

Results are encouraging that for patients with advanced liver cancer and portal vein thrombosis. 1 of 23. All patients died

29Final Conclusions

The relationship between vitamin K and cancer30Vitamins A and D but not E and K decreased the cell number in human pancreatic cell lines

B. Ohlsson, E. Albrechtsson & J. Axelson

31Overview Study designExperimentalSeven pancreatic cancer cell linesObjectiveLocation

-The seven cell lines used were established from patients operated onfor pancreatic adenocarcinoma. Objective: The aim of the present study was to evaluate the effect of fat-soluble vitamins on the growth ofpancreatic cancer cells.Location: Malmo, sweden Lund University hospital Method: Specimens from patients operated on for pancreatic cancer were used to establish primary cultures from which cell lineswere developed, The cells were maintained as a monolayer culture in Dulbecco modified Eagle medium, with 10% fetal calf serum (FCS) (GIBCO) and 1%penicillin streptomycin solution at 37 C under 95% air and 5% CO2. Seven cell lines with continuous growth were used in the different dose response studies.

Results: 32Method and Statistics MethodDescriptive statisticsMeanStandard deviation Inferential Statistics Kruskal-Wallis testMann-Whitney U test Method: Specimens from patients operated on for pancreatic cancer were used to establish primary cultures from which cell lineswere developed, The cells were maintained as a monolayer culture in Dulbecco modified Eagle medium, with 10% fetal calf serum (FCS) (GIBCO) and 1% penicillin streptomycin solution at 37 C under 95% air and 5% CO2. Seven cell lines with continuous growth were used in the different dose response studies. VitaminK1 is one of the natural vitamin K compounds.It was dissolved in ethanol, and further diluted in serum-free. The cell number was measured after 48 h incubation withthe different vitamin solutions.

33Results

Vitamin K1 increased the cell number by 15%-80% in 3 of the 7 cell lines tested Most potent stimulatory were seen in lines 10 -10 and 10 -7

34Strengths and WeaknessesStrengths Purpose Evidence of planning and organization Statistics clearly stated

Weaknesses Weaknesses Controlled environment Statistics Future research

Purpose: the aim of the present study was to assess the clinical efficacy of high dose K3 in the treatment of patients with advanced liver cancer Evidence: Experiment could be completed again Stats clearly stated through 3 tables Population: large age range, both males and females

Demographics: all from India Population: All are in stage three liver cancer Sample size: 42 35Verdict Vitamin K1No relationshipVitamin K2Lung cancer incidenceProstate cancer incidence Overall cancer mortality Vitamin K3 More research needed

More research is needed for each vitamin, there needs to be more studies done on one type of cancer and not a variety at once. Vitamin K has no association with cancer mortality or incidence. There were few studies that have been conducted in the United states Vitamin K2: association with aboveK3: more research is needed 36Future Direction American Cancer SocietyVitamin K1 and K2 (Nimptsch et al., 2010) BiomarkersMore studies in humansVitamin K3 (Sarin et al., 2006). Larger studies Different dosages

ACS: believe that looking at larger studies may not be very useful for looking at the effects of VK intake. No evidence available of significant effect. K3 injections arent safe. Some people have allergic reactions, numbness in arms and legs, chest pains, shortness of breath. No planned research is set as of now. Limited accuracy of determining how much vitamin k is in a food item. More studies before recommendation can be made for prevention.

From article #2: pursuing further studies with larger numbers of patients to define the exact role of high dose K3 in patients with advanced liver cancer and portal vein thrombosis. Assessment of different dosages and longer treatment schedules in patients 37Any questions?

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