Naturally occurring K vitamins inhibit pancreatic cancer cell survival through a caspase-dependent pathway

Department of Surgery, Jefferson Center for Pancreatic, Biliary and Related Cancers, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Journal of Gastroenterology and Hepatology (Impact Factor: 3.5). 11/2009; 25(4):738-44. DOI: 10.1111/j.1440-1746.2009.06085.x
Source: PubMed


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.

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    • "There are two natural forms of vitamin K, vitamin K1 (VK1, mostly found in green leafy vegetables) and vitamin K2 (VK2, synthesized by the intestinal flora). It has been shown that vitamin Ks could inhibit the growth of various types of cancer cells in vitro as a single agent or in combination with other chemotherapy [16,17]. Recent studies have shown that VK1 can enhance the effects of sorafenib-mediated hepatocellular carcinoma cell growth inhibition through inhibiting the density-enhanced phosphatase 1 (DEP-1)-regulated c-Met-Akt pathway [18]. "
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    ABSTRACT: Background The combined effects of anticancer drugs with nutritional factors against tumor cells have been reported previously. This study characterized the efficacy and possible mechanisms of the combination of sorafenib and vitamin K1 (VK1) on glioma cell lines. Methods We examined the effects of sorafenib, VK1 or their combination on the proliferation and apoptosis of human malignant glioma cell lines (BT325 and U251) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, flow cytometry and 4′,6-diamidino-2-phenylindole (DAPI) assay. The signaling pathway changes were detected by western blotting. Results Sorafenib, as a single agent, showed antitumor activity in a dose-dependent manner in glioma cells, but the effects were more pronounced when used in combination with VK1 treatment. Sorafenib in combination with VK1 treatment produced marked potentiation of growth inhibition and apoptosis, and reduced expression of phospho-mitogen-activated protein kinase kinase (MEK) and phospho-extracellular signal-regulated kinase (ERK). Furthermore, the expression levels of antiapoptotic proteins Bcl-2 and Mcl-1 were significantly reduced. Conclusions Our findings indicated that VK1 enhanced the cytotoxicity effect of sorafenib through inhibiting the Raf/MEK/ERK signaling pathway in glioma cells, and suggested that sorafenib in combination with VK1 maybe a new therapeutic option for patients with gliomas.
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    ABSTRACT: Vitamin K4 (VK4) is a synthetic hydrophilic menadione compound, which is clinically used as hemostasis medicine. It has been reported that several vitamin Ks had inhibitory effects on various cancer cells. However, there is no report about VK4s anticancer activity. The goal of this study was to investigate the inhibitory effect of VK4 on human prostate PC-3 cells and the mechanisms involved. We found that VK4 dose-dependently inhibited cell proliferation in PC-3 cells with an IC50 value of about 20.94 microM. Hoechst 33258 Staining results showed that VK4 caused DNA fragmentation in PC-3 cells. PI staining results indicated that VK4-induced PC-3 cell cycle arrest at the S phase. Further mechanistic studies revealed that VK4-mediated induction of apoptosis in PC-3 cell is associated with disruption of mitochondrial membrane potential, down-regulation of Bcl-2, and up-regulation of Bax, release of cytochrome c from mitochondria, and activation of caspase-3 and PARR Thus, VK4 might be useful in prostate cancer chemotherapy.
    No preview · Article · Jun 2013 · Pharmazie
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    ABSTRACT: Vitamin K1 has been demonstrated as having anticancer potentiality mainly in liver cancer cells. Beyond the reported mechanisms of cancer inhibition (cell cycle arrest and induction of apoptosis), a possible control by vitamin K1 on molecules affecting cell growth could be hypothesized. In the literature, few (if any) data are available on its antitumor effects on colon cancer cells. Therefore, the aims of the study were to investigate in three differently graded human colon cancer cell lines (Caco-2, HT-29, and SW480) the effects of increasing concentrations of vitamin K1 (from 10 μM to 200 μM) administered up to 72 h on (1) cell proliferation, (2) apoptosis with the possible involvement of the MAPK pathway, and (3) polyamine biosynthesis. Vitamin K1 treatment caused a significant antiproliferative effect and induced apoptosis in all the cell lines, with the involvement of the MAPK pathway. A concomitant and significant decrease in the polyamine biosynthesis occurred. This is the first study demonstrating a significant polyamine decrease in addition to the antiproliferative and proapoptotic effects following vitamin K1 administration to colon cancer cell lines. Therapeutically, combinations of vitamin K1 with polyamine inhibitors and/or analogues may represent a suitable option for chemoprevention and/or treatment in future strategies for colorectal cancer management.
    Full-text · Article · May 2015
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