vitamin-k-1 and Pancreatic-Neoplasms

No epidemiologic studies have been conducted to assess the association of intake of dietary vitamin K with the risk of pancreatic cancer. We used prospective data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial between 1993 and 2009 to fill this gap. A total of 101,695 subjects were identified. Dietary intakes of phylloquinone (vitamin K1), menaquinones (vitamin K2), and dihydrophylloquinone (dihydrovitamin K1) were assessed using a food frequency questionnaire. Cox regression was applied to calculate hazard ratios and 95% confidence intervals. During a mean follow-up of 8.86 years (900,744.57 person-years), 361 cases of pancreatic cancer were documented. In the fully adjusted model, dietary intakes of phylloquinone (for quartile 4 vs. quartile 1, hazard ratio (HR) = 0.57, 95% confidence interval (CI): 0.39, 0.83; P for trend = 0.002) and dihydrophylloquinone (for quartile 4 vs. quartile 1, HR = 0.59; 95% CI: 0.41, 0.85; P for trend = 0.006), but not menaquinones (for quartile 4 vs. quartile 1, HR = 0.93; 95% CI: 0.65, 1.33; P for trend = 0.816), were found to be inversely associated with the risk of pancreatic cancer in a nonlinear dose-response manner (all P values for nonlinearity < 0.05), and this was not modified by predefined stratification factors and remained in sensitivity analyses. In conclusion, dietary intakes of phylloquinone and dihydrophylloquinone, but not menaquinones, confer a lower risk of pancreatic cancer. Future studies should confirm our findings.

Topics: Aged; Clinical Trials as Topic; Diet; Diet Surveys; Female; Humans; Male; Middle Aged; Nutritional Status; Pancreatic Neoplasms; Proportional Hazards Models; Prospective Studies; Risk Factors; United States; Vitamin K 1; Vitamin K 2

Available medical therapies against pancreatic cancer are largely ineffective and have many side-effects. Physiologically, vitamins K1 and K2 (VK) act as co-factors for gamma-carboxylation of prothrombin and other coagulation factors. In previous studies, VK analogs have been found to have potent negative effects on the survival of various cancer cells. We hypothesized that the well-tolerated and naturally occurring VK1 and VK2 may be used to inhibit pancreatic cancer cell survival.. Four pancreas cancer cell lines were tested. Two of these (MiaPaCa2 and PL5) were found to be sensitive to VK1 and VK2 (IC50 values < or =150 microM). To address the mechanisms of this effect on cell survival, we performed cell cycle and apoptosis studies using VK2 (the more potent compound).. We found that VK induced caspase-dependent apoptosis in over 60% of cells in the sensitive lines at the half maximal inhibitory concentration (IC(50)) range. Further, this induction in apoptosis was antagonized by a caspase inhibitor. Accompanying apoptosis, a dose- and time-dependent induction of extracellular signal-regulated kinase (ERK) phosphorylation occurred when sensitive lines were treated with either VK1 or VK2 at inhibitory doses. Simultaneous co-treatment of cells with a MEK1 inhibitor and VK prevented both the induction of ERK phosphorylation and the apoptosis, showing that the mitogen-activated protein (MAP) kinase pathway is central for VK-mediated apoptosis in pancreatic cancer cells.. These data show that naturally-occurring, non-toxic K vitamins can inhibit the survival of some pancreatic cancer cell lines. These novel, safe and clinically-utilized agents initiate a caspase-dependent apoptosis via the MAP kinase pathway and could potentially benefit patients with pancreatic cancer either as a single agent or in combination with chemotherapy for treatment, or for prevention of recurrence of pancreas cancer post resection.

Topics: Antineoplastic Agents; Apoptosis; Caspase Inhibitors; Caspases; Cell Cycle; Cell Line, Tumor; Cell Survival; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Humans; Inhibitory Concentration 50; MAP Kinase Kinase 1; Pancreatic Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Signal Transduction; Time Factors; Vitamin K 1; Vitamin K 2

Apoptosis has been shown to be induced by many agents, including the clinically useful Sorafenib and K vitamins (VKs). Since few agents have activity against pancreas cancer cell growth, we evaluated the role of naturally occurring K vitamins and Sorafenib both independently and together on the growth in culture of pancreas adenocarcinoma cell lines, including PL-5, PANC-1, and MIA PaCa-2. We found that when a K vitamin was combined with Sorafenib, the dose of Sorafenib required for growth inhibition was substantially reduced. Furthermore, growth could be inhibited at doses of each VK plus Sorafenib in combination that were ineffective when used alone. This effect was seen using vitamins K1, K2, and K5. The combination of VK1 plus Sorafenib-induced apoptosis, as determined by both FACS and TUNEL staining. Phospho-ERK and Bcl-2 levels were decreased, but not levels of other bcl-2 family members. Cleavage of caspases 3 and 8, PARP and Bid were all induced by this combination. Vitamin K1 plus Sorafenib combination also resulted in elevated levels of activated c-Jun N-terminal kinase (JNK) and its substrates c-Jun and FasL. JNK inhibition partly antagonized the induction of apoptosis. Thus, combination VK1 plus Sorafenib strongly induced growth inhibition and apoptosis in pancreas cancer cells, involving both inhibition of the RAF/MEK/ERK pathway as well as activation of the JNK, c-Jun and FasL apoptotic pathway. Since both agents are available for human use, the combination is attractive for evaluation against pancreas cancer growth in vivo.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzenesulfonates; BH3 Interacting Domain Death Agonist Protein; Caspase 3; Caspase 8; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Fas Ligand Protein; Fas-Associated Death Domain Protein; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Niacinamide; Pancreatic Neoplasms; Phenylurea Compounds; Phosphorylation; Poly(ADP-ribose) Polymerases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-jun; Pyridines; raf Kinases; Sorafenib; Vitamin K 1

Topics: Aged; Bile; Carcinoma; Chromatography, Thin Layer; Feces; Humans; Injections, Intravenous; Male; Middle Aged; Pancreatic Neoplasms; Pancreatitis; Tritium; Vitamin K 1

Topics: Bile; Bile Duct Neoplasms; Biliary Tract; Biliary Tract Diseases; Cholangiography; Cholelithiasis; Cholestasis; Contrast Media; Diagnosis, Differential; Female; Gallstones; Hemorrhage; Hepatitis; Humans; Liver Diseases; Male; Methods; Neoplasm Metastasis; Pancreatic Neoplasms; Peritonitis; Prothrombin Time; Vitamin K 1