Thursday, 6 February 2014

Breast cancer in Vitamin K's Points of View

By Kyle J. Norton

Vitamin K(K1, phylloquinone; K2, menaquinones), is a fat soluble vitamin, found abundantly in leafy green vegetables, broccoli, and Brussels sprouts, etc. It is best known for promotion of coagulation and bone health.
Epidemiological studies focused in the synthetic version of vitamin K(Vk3) in reduced risk and treatment of breast cancer have proven successful in certain extents. In comparison of the anti cancer effects of Vitamin K (VK) congeners, vitamin K3(Menadione ), a synthetic analogue with the same properties as provitaminis was found to be most potent in treating various types of cancer, including breast cancer(1) In comparison the inhibition effects of vitamin K, K3 and warfarin in human cancer cell lines, the combination of 3 Completely inhibited of L1210 growth in flask culture at concentrations of 200 micrograms/ml of warfarin, 75 micrograms/ml of vitamin K1, and 4 micrograms/ml of vitamin K3. The combination K3 and warfarin enhanced cytotoxicity at doses depending manner. Vitamin K3 alone was also cytotoxic in a concentration of 1 micrograms/ml, including breast cancers(1a). Synthesized VK2 derivatives (MQ-1, MQ-2 and MQ-3, also in the comparison of the antitumor activities of vitamin K1, K2, and K3 against a panel of human cancer cell lines, vitamin K3 showed inhibition of various cancers and radioresistant cancers including breast cancer cell lines (BC-M1)( in doeses of 26, 15, 25, and 33 microM: VK1 ranged from 6 to 9 mM, and VK2 ranged from 1 to 2 mM in ID50 values(1b).

In breast cancer, vitamin K3 analogue plumbagin exerted its inhibitor effect in osteoclastogenesis induced by tumor cells and breast cancer-induced osteolytic metastasis through suppression of RANKL signaling to alter tumor progression(2). In breast cancer cell line MCF-7, VK(3), it exhibited cytotoxicity through DNA fragmentation (separation or breaking of DNA strands into pieces) and mitochondrial dysfunction(3).
In MCF-7, estrogen receptor-positive breast cancer cells, vitamin K3 (menadione) inhibited the transcriptional activity of 17beta-estradiol in a reporter gene assay(4). CR108, a novel vitamin K3 derivative, (S)-2-(2-hydroxy-3-methylbutylthio)naphthalene-1,4-dione, exhibited apoptosis in both the non-HER-2-overexpressed MCF-7 and HER-2-overexpressed BT-474 breast cancer cells, through induced the loss of mitochondrial membrane potential, leading to cytochrome c released from mitochondria to cytosol and and cleaved PARP(activate CNS immune responses) proteins(5). Menadione, also known as VK3, its reduction-oxidation, generated by ascorbate-driven menadione redox cycling inhibited MCF7 breast cancer cells, through glycolysis(metabolic pathway for generation of energy) inhibition, loss of calcium homeostasis(maintains adequate calcium levels), DNA damage and changes in mitogen activated protein kinases (MAPK)(regulate proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis ) activities(6). Also, in MCF 7 breast cancer cells, Fluorinated Cpd 5, an arylating K-vitamin derivative, showed growth inhibition probably via conjugation of cellular thiols, by suppressing the activity of thiol containing cellular protein tyrosine phosphatase (PTP) enzyme(play critical roles in fundamental biological processes), with consequent induction of various tyrosine phosphoproteins(involved in a number of metabolic and signalling pathways) in promoting mutation cell proliferation(7).

Vitamin K although was found effectively in decreased risk and treatment for breast cancers by exhibition of its effects in cytotoxicity, apoptosis and anti proliferation through DNA fragmentation, mitochondrial dysfunction, cell death pathway, overdoses can induce symptoms of Skin rash,  Diarrhea, Nausea, Vomiting, Anemia, etc. Please make sure you follow the guideline of the Institute of Medicine of the National Academies.

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(1) Comparison of antitumor activity of vitamins K1, K2 and K3 on human tumor cells by two (MTT and SRB) cell viability assays by Wu FY, Liao WC, Chang HM.(PubMed)
(1a) Vitamin K3 inhibition of malignant murine cell growth and human tumor colony formation. by Chlebowski RT, Dietrich M, Akman S, Block JB.(PubMed)
(1b) Vitamin K2-derived compounds induce growth inhibition in radioresistant cancer cells by Amalia H, Sasaki R, Suzuki Y, Demizu Y, Bito T, Nishimura H, Okamoto Y, Yoshida K, Miyawaki D, Kawabe T, Mizushina Y, Sugimura K(PubMed).
(2) Plumbagin inhibits osteoclastogenesis and reduces human breast cancer-induced osteolytic bone metastasis in mice through suppression of RANKL signaling by Sung B, Oyajobi B, Aggarwal BB.(PubMed)
(3) The potential of vitamin K3 as an anticancer agent against breast cancer that acts via the mitochondria-related apoptotic pathway by Akiyoshi T, Matzno S, Sakai M, Okamura N, Matsuyama K.(PubMed)
(4) Anti-estrogenic activity of fifty chemicals evaluated by in vitro assays by Jung J, Ishida K, Nishihara T.(PubMed)
(5) CR108, a novel vitamin K3 derivative induces apoptosis and breast tumor inhibition by reactive oxygen species and mitochondrial dysfunction by Yang CR, Liao WS, Wu YH, Murugan K, Chen C, Chao JI.(PubMed)
(6) Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells by Beck R, Verrax J, Dejeans N, Taper H, Calderon PB.(PubMed)
(7) Growth inhibition and protein tyrosine phosphorylation in MCF 7 breast cancer cells by a novel K vitamin by Kar S, Carr BI.(PubMed)

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