vitamin-k-semiquinone-radical and Pancreatic-Neoplasms

Although there is increasing evidence that vitamins influence pancreatic adenocarcinoma biology and carcinogenesis, a comprehensive review is lacking. In this study, we performed a PubMed literature search to review the anticancer mechanisms and the preclinical and clinical studies that support the development of the bioactive vitamins A, C, D, E, and K in pancreatic cancer intervention. Preclinical studies have shown promising results for vitamin A in pancreatic cancer prevention, with clinical trials showing intriguing responses in combination with immunotherapy. For vitamin C, preclinical studies have shown slower tumor growth rates and/or increased survival when used alone or in combination with gemcitabine, with clinical trials with this combination revealing decreased primary tumor sizes and improved performance status. Preclinical studies with vitamin D analogues have shown potent antiproliferative effects and repression of migration and invasion of pancreatic cancer cells, with a clinical trial showing increased time to progression when calciferol was added to docetaxel. For vitamin E, preclinical studies have shown that δ-tocotrienol and γ-tocotrienol inhibited tumor cell growth and survival and augmented gemcitabine activity. Early-phase clinical trials with δ-tocotrienol are ongoing. Vitamin K demonstrates activation of apoptosis and inhibition of cellular growth in pancreatic tumor cells; however, there are no clinical studies available for further evaluation. Although preclinical and clinical studies are encouraging, randomized controlled trials with endpoints based on insights gained from mechanistic and preclinical studies and early-phase clinical trials are required to determine the efficacy of bioactive vitamin interventions in pancreatic cancer.

Topics: Adenocarcinoma; Apoptosis; Ascorbic Acid; Cell Proliferation; Combined Modality Therapy; Dietary Supplements; Humans; Neoplasm Invasiveness; Pancreatic Neoplasms; Survival Rate; Vitamin A; Vitamin D; Vitamin E; Vitamin K; Vitamins

The coagulation function in patients with pancreatic carcinoma is abnormal and the reason is not very clear. In this study, we retrospectively analyzed the coagulation function in patients with pancreatic carcinoma.. From June 2004 to December 2007, 132 patients received diagnosis and treatment in our hospital. The coagulative parameters including the prothrombin time, activated partial thromboplastin time, and fibrinogen levels were collected and studied retrospectively.. The average fibrinogen levels in patients with pancreatic carcinoma, (476.21 +/- 142.05) mg/dl, were significantly higher than in patients with cholangiolithiasis, (403.28 +/- 126.41) mg/dl (P < 0.05). In patients with pancreatic carcinoma, the levels of fibrinogen in the group with jaundice were significantly higher than in patients without jaundice (P < 0.05). In patients who received Pancreaticoduodenectomy, Whipple's operation, the level of fibrinogen in the group with local invasiveness was significantly higher than in the group without invasiveness. The group with lymphatic metastasis had higher levels than the group without lymphatic metastasis (P < 0.05). There was no significant difference of intraoperative blood loss between patients with vitamin K, (748.27 +/- 448.51) ml, and those without vitamin K, (767.31 +/- 547.89) ml (P > 0.05).. The level of fibrinogen in patients with pancreatic carcinoma was elevated. The elevated fibrinogen level may be associated with invasiveness and lymphatic metastasis. Using vitamin K in perioperation management did not reduce intraoperative blood loss.

Topics: Adult; Aged; Aged, 80 and over; Blood Coagulation; Cholelithiasis; Female; Fibrinogen; Humans; Jaundice; Lymphatic Metastasis; Male; Middle Aged; Pancreatic Neoplasms; Pancreaticoduodenectomy; Retrospective Studies; Vitamin K; Young Adult

The four fat-soluble vitamins A, D, E and K have been tested in experimental and human studies to assess their influence on the growth of cancer cells of different origins. Receptors for vitamin A and D have been detected on pancreatic cancer cells, and analogues of these reduced the cell number in vitro. The aim of the present study was to evaluate the effect of fat-soluble vitamins on the growth of pancreatic cancer cells.. The seven cell lines used were established from patients operated on for pancreatic adenocarcinoma. The effect of incubation with the vitamin A analogues all-trans-retinoic acid (atRA;tretinoin) and 9-cis-retinoic acid (9-cis-RA), the synthetic vitamin D analogue EB 1089, vitamin E succinate and K on the cell number was examined by the XTT method.. The vitamin A and D analogues decreased the pancreatic cancer cell number when high concentrations of 10 - 10 M were administered. A combination of retinoids and the vitamin D analogue EB 1089 did not enhance the effect. Vitamin E succinate inhibited cell growth to a small extent (maximal 26%) in 3 out of 7 cell lines, whereas vitamin K increased the pancreatic cancer cell number in 3 out of 7 cell lines.. High concentrations of vitamin A and D analogues decreased the cell number in pancreatic cancer cell lines. Vitamin E succinate and K did not have this effect. In the treatment of pancreatic cancer, further exploration of vitamin D analogues could be fruitful.

Topics: Adenocarcinoma; Cell Count; Cell Proliferation; Dose-Response Relationship, Drug; Female; Humans; Male; Pancreatic Neoplasms; Probability; Reference Values; Sensitivity and Specificity; Tumor Cells, Cultured; Vitamin A; Vitamin D; Vitamin E; Vitamin K

In this study, we examined the effects of vitamin K(2) (menaquinone 4), which has a geranylgeranyl side chain, on various lines of cells derived from human solid tumors and compared them with the effects of geranylgeraniol (GGO).. Cell proliferation was determined with 3'-[1-[(phenylamino)carbonyl]-3,4-tetrazolium- bis (4-methoxy-6-nitro) benzene-sulfonic acid hydrate (XTT), and the induction of apoptosis was analyzed by TUNEL staining and flow cytometry as well as by measurement of DNA fragmentation, released nucleosomes and caspase-3 activity. Levels of Bcl-2, Bax and cytochrome c were determined by immunoblotting.. GGO inhibited the growth of all eight cell lines derived from solid tumors, while vitamin K(2) selectively inhibited the proliferation of ovarian TYK-nu and pancreatic MIA PaCa-2 cancer cells, inducing apoptosis in both cell lines. Far more time was required for the induction of apoptosis in these two cell lines by vitamin K(2) than by GGO. Apoptotic signals induced in TYK-nu cells during the first 2 days that followed the addition of vitamin K(2) to the culture medium were reversible, but these signals became irreversible after 3 days of treatment with vitamin K(2). The induction of apoptosis in TYK-nu cells by vitamin K(2) was inhibited by cycloheximide and also by starvation at a low concentration of serum. Neither cycloheximide nor starvation had any effect on the induction of apoptosis by GGO. Cytochrome c was released simultaneously with the initiation of apoptosis on treatment of TYK-nu cells with vitamin K(2) or GGO. However, GGO induced the release of cytochrome c from isolated mitochondria, while vitamin K(2) did not. The amount of Bcl-2 in TYK-nu cells was reduced by vitamin K(2), but not by GGO.. In contrast to GGO, vitamin K(2) induced apoptosis selectively in pancreatic MIA-PaCa 2 and ovarian TYK-nu cancer cells. It is suggested that de novo protein synthesis might be necessary for induction of apoptosis by vitamin K(2) but not by GGO, and thus, that vitamin K(2) and GGO might induce apoptosis by different mechanisms.

Topics: Apoptosis; bcl-2-Associated X Protein; Caspase 3; Caspases; Cell Division; Cell Separation; Cytochrome c Group; Diterpenes; DNA Fragmentation; Female; Flow Cytometry; Humans; In Situ Nick-End Labeling; Male; Mitochondria; Ovarian Neoplasms; Pancreatic Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured; Vitamin K

gamma-Carboxylated proteins were detected in normal human pancreas by immunohistochemistry with a monoclonal antibody (M3B) specific for gamma-carboxyglutamyl residues. Staining appeared to be localized to the glucagon-secreting alpha-cells in the islets of Langerhans. Consistent with this, sections from a glucagonoma were stained much more intensely with the M3B antibody than those from an insulinoma. A murine alpha-cell line (alphaTC1 Clone 9) was cultured and gamma-carboxylated polypeptides, identified immunologically as prothrombin, protein S and (tentatively) Gas6, were isolated from the intracellular compartment by chromatography on an M3B-coupled resin. As in liver, prothrombin is synthesized by alpha-cells as a gamma-carboxylated zymogen that can be cleaved by ecarin to form an active serine protease that is inhibited by hirudin. The pancreas thus appears to be a novel site of synthesis for certain vitamin K-dependent proteins.

Topics: 1-Carboxyglutamic Acid; Animals; Antibodies, Monoclonal; Clone Cells; Glucagonoma; Humans; Immunohistochemistry; Insulinoma; Islets of Langerhans; Mice; Pancreatic Neoplasms; Protein Biosynthesis; Protein S; Proteins; Prothrombin; Vitamin K

In the present study, we show that 2-(2-hydroxyethylsulfaryl)-3-methyl-1,4-naphthoquinone, or CPD 5, is a potent growth inhibitor for pancreas cancer cell lines (ID(50): 21.4 +/- 3.8, 31.8 +/- 2.7 and 55.2 +/- 4.5 microM for MiaPaCa, Panc-1 and BxPc3, respectively). It induced protein tyrosine phosphor-ylation of hepatocyte growth factor (HGF) receptor (c-Met) or epidermal growth factor receptor (EGFR), which increased progressively to a maximum level at 30 min in Panc-1 cells. The receptor phosphorylation by CPD 5 was indicated to be functional, since these receptors were found to bind with Grb2 or SOS1 protein. CPD 5 was also suggested to induce phosphorylation of external signal-regulated kinase (ERK). EGF induced cell proliferation through ERK phosphorylation, since U0126, which is an inhibitor of ERK phosphorylation, abrogated the increase of cyclin D1 by EGF. HGF increased the amount of p27 protein, suggesting that it is associated with cell differentiation. By contrast, U0126 reduced CPD 5-induced cell death. On two-dimensional electrophoresis, we found an extra type of phospho-ERK, and this was completely and selectively abolished by U0126. These results suggest that ERK phosphorylation, especially the extra spot on two-dimensional gel, is critically associated with CPD 5-mediated cell death.

Topics: Antineoplastic Agents; Cell Death; Cell Division; Cyclin D1; Epidermal Growth Factor; ErbB Receptors; Hepatocyte Growth Factor; Humans; Microfilament Proteins; Mitogen-Activated Protein Kinases; Muscle Proteins; Naphthoquinones; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-met; Tumor Cells, Cultured; Vitamin K

This study evaluated the action of menadione on cell proliferation and integrity of the rat pancreatic acinar cell line, AR4-2J. Menadione at 1-20 microM dose- and time-dependently inhibited cell proliferation of AR4-2J cells. In contrast, a high concentration of menadione (100 microM) caused rapid cell death (> 90% of cells took up trypan blue within 4-h). While the high concentration of menadione (100 microM) induced DNA smear in electrophoresis indicative of necrosis, lower concentrations (10-20 microM) induced a DNA ladder indicative of apoptosis. Similar results were obtained using a DNA fragmentation ELISA. Glutathione (1 mM), the calcium chelator EGTA (500 microM), and the cysteine protease inhibitor NCO-700 (5 mM) partly inhibited the effect of 1-10 microM menadione on cell proliferation and DNA fragmentation. Menadione at 1-20 microM induced wild-type P53, whereas the 100 microM menadione had a minor effect on wild-type P53. It is concluded that menadione induced necrosis at high concentrations and apoptosis at low concentrations in AR4-2J cells. Apoptosis induced by lower concentrations of menadione may be mediated by wild-type P53, intracellular calcium, and mechanisms which decrease the intracellular concentration of reduced glutathione.

Topics: Animals; Apoptosis; Blotting, Western; Cell Division; DNA Fragmentation; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Necrosis; Pancreas; Pancreatic Neoplasms; Rats; Tumor Cells, Cultured; Vitamin K

In human erythrocytes, in which the fractional turnover rate of glucose 6-phosphate is rather low, menadione increases to almost the same relative extent the oxidation of D-[U-14C]glucose and D-[U-14C]galactose. However, in pancreatic tumoral islet cells (RINm5F line), in which the fractional turnover rate of glucose 6-phosphate is considerably higher, menadione increases the oxidation of D-[1-14C]glucose but not that of D-[1-14C]galactose. These results suggest that alpha-D-glucose 6-phosphate generated from exogenous D-galactose is channeled preferentially into the glycolytic rather than pentose phosphate pathway. Such was no more the case, however, when the RINm5F cells were exposed simultaneously to both D-glucose and D-galactose.

Topics: Adenoma, Islet Cell; Erythrocytes; Galactose; Glucose-6-Phosphate; Glucosephosphates; Glycolysis; Humans; Pancreatic Neoplasms; Vitamin K

Topics: Antineoplastic Agents; Colonic Neoplasms; Energy Transfer; Humans; Melanoma; Naphthols; Neoplasms; Pancreatic Neoplasms; Skin Neoplasms; Vitamin K

Topics: Adenocarcinoma; Adenoma, Bile Duct; Adult; Aged; Bile; Bile Duct Neoplasms; Bile Ducts; Biliary Tract Diseases; Bilirubin; Carbon Isotopes; Enzymes; Fats; Female; Humans; Intestinal Absorption; Lymph; Male; Middle Aged; Pancreatic Neoplasms; Solubility; Thoracic Duct; Thymol; Time Factors; Tritium; Vitamin A; Vitamin D; Vitamin E; Vitamin K

Topics: Analgesics; Bile Duct Neoplasms; Cholangiography; Cholelithiasis; Cysts; Dexamethasone; Gallbladder Neoplasms; Humans; Liver Neoplasms; Neoplasm Metastasis; Pancreatic Neoplasms; Penicillins; Postoperative Care; Prednisolone; Preoperative Care; Stomach Neoplasms; Vitamin K