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The anticancer effects of vitamin K

Alternative Medicine Review, August, 2003 by Davis W. Lamson, Steven M. Plaza

Abstract

Vitamin K, an essential nutrient often associated with the clotting cascade, has been the focus of considerable research demonstrating an anticancer potential. Much of this research has focused on vitamin K3, although vitamins K2 and K1 have also been shown to have anticancer effects. Early studies of vitamin K3 employed an oxidative model to explain the anticancer effects seen in both in vitro and in vivo studies; however, this model does not adequately address the action of vitamins K1 and K2. Recent research has demonstrated the anticancer action of vitamin K may act at the level of tyrosine kinases and phosphatases, modulating various transcription factors such as Myc and Fos. Tyrosine kinases associated with cyclins have also been shown to be affected by vitamin K, which can lead to cell cycle arrest and cell death. (Altern Med Rev 2003;8(3):303-318)

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Introduction

After earlier research, a purified form of vitamin K, phylloquinone, was isolated from plants in 1939 and used to treat a nutritional deficiency characterized by decreased prothrombin levels. Henrick Dam received the Nobel Prize in 1943 for his discovery of vitamin K (the "koagulations" vitamin). The role of vitamin K as a cofactor in normal blood coagulation stems from the post-translational modification of a number of plasma proteins such as factors II (prothrombin), VII, IX, X, as well as proteins C, S, and Z. Vita min K, in its reduced hydroquinone form, acts as a cofactor in the enzymatic carboxylation by gamma-glutamyl-carboxylase of glutamic acid residues forming gamma-carboxyglutamic acid in plasma proteins. (1) In the process of carboxylation, vitamin K epoxides (2,3 epoxides) are formed, which are reduced back to vitamin K by thiols and epoxide reductases. Thus, vitamin K cycles from an epoxide to a quinone and back to the hydroquinone for another gamma-carboxylation reaction. The drug Coumadin[R] (warfarin) inhibits vitamin K epoxide reductase, interfering with the reduction of the epoxide and halting the cycling back to the hydroquinone intermediate, thereby interrupting the activation of blood coagulation factors. (2)

Although vitamin K is usually identified as a critical factor in blood coagulation, recent research has found that vitamin K is also a cofactor in bone metabolism. (3-9) Inhibition of cancerous cell growth in vivo and in vitro by vitamin K has also been observed. (10-17) Examination of this latter phenomenon, its mechanism and related concepts, comprises the balance of this paper.

Vitamin K-Dependent Receptors

The role of vitamin K as a cofactor in the carboxylation of gamma-carboxyglutamyl protein residues has expanded to include a new class of vitamin K-dependent receptor:ligand systems critical to aspects of cellular metabolism. Several vitamin K-dependent proteins have been identified as specific ligands for receptur tyrosine kinases (RTKs) that are important in a number of cell signaling processes such as cellular survival, transformation, and replication). (18)

Growth-arrest-specific gene-6 (Gas6) is an example of a vitamin K-dependent protein ligand that increases in growth-arrested cells. (19) Protein S, like Gas6, also acts as an RTK ligand. After translation Gas6 protein is carboxylated via a vitamin K-dependent process in the endoplasmic reticulum. This post-translational modification enables Gas6 to bind to a number of receptor protein tyrosine kinases such as Axl (also designated as Ufo or Ark), Sky (also designated Dtk, Tyro3, Rsc, Brt, Etk2, or Tif), and Mer (also Eyk or Tyro12) that make up a new subfamily of vitamin K-dependent receptor tyrosine kinases). (20 21) Various names have been assigned to the same re ceptors because they were described by different investigators using a number of cell lines. Recently, many have been found to be identical. A major function of Gas6-Ark signaling involves increased cell survival under conditions that do not allow cell proliferation. (22) Although the exact function of Gas6 protein is not yet fully defined, it is believed it may act as a physiological anti-inflammatory. (23) It is also part of a mechanism for clearing away apoptotic and dying cells by helping phagocytic cells to recognize phosphatidylserine-expressing cells. (24)

This newly discovered subfamily of receptor tyrosine kinases has also been associated with cell growth regulation and tumorigenesis. Discussions of vitamin K-dependent proteins related to lymphoid malignancy, (25) lung malignancy, and multiple myeloma (26) have been published. While they were not related to possible treatment of malignancy with vitamin K derivatives, they are mentioned here for completeness.

Vitamin K Structure

Vitamin K is a family of structurally similar fat-soluble 2-methyl- 1,4-naphthoquinones, including phylloquinone (K1), menaquinones (K2), and menadione (K3). 1,4-Naphthoquinones form a family of compounds characterized by a naphthalene ring containing two carbonyl moieties at positions 1 and 4, which in the case of vitamin K is substituted at positions 2 and 3 (Figures 1 3). All members of the vitamin K family possess the identical napthoquinone skeleton with various side chains that distinguish them. The best-known member of the vitamin K family is phylloquinone, also known as phytonadione or menaphthone, so named because of its intimate relationship with photosynthesis in plant leaves. Phylloquinone is found in many higher plants as well as algae, with the highest concentrations found in green leafy vegetables). (27)

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The anticancer effects of vitamin K

Alternative Medicine Review, August, 2003 by Davis W. Lamson, Steven M. Plaza

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