title: Naturally occurring K vitamins inhibit pancreatic cancer cell survival through a caspase-dependent pathway.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, Jefferson Center for Pancreatic, Biliary and Related Cancers, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Shayna L
authors.initials: SL
authors.lastname: Showalter
authors.forename: Ziqiu
authors.initials: Z
authors.lastname: Wang
authors.forename: Christina L
authors.initials: CL
authors.lastname: Costantino
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Yeo
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Brody
authors.forename: Brian I
authors.initials: BI
authors.lastname: Carr
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D010837:Vitamin K 1 / Q000494:pharmacology*; D024482:Vitamin K 2 / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D047428:Protein Kinase Inhibitors; D024482:Vitamin K 2; D010837:Vitamin K 1; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020169:Caspases