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Vitamin K2 appears to treat some cancers – April 2018

Research progress on the anticancer effects of vitamin K2 (Review)

Oncology Letters, Pages:8926-8934 online on: April 16, 2018 https://doi.org/10.3892/ol.2018.8502
Fan Xv Jiepeng Chen Lili Duan Shuzhuang Li

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Figure 1. Inhibition of the proliferation of cancer cells by VK2 and induction of cell differentiation in cancer cells by VK2. VK2 inhibits the proliferation of cancer cells by inducing cell-cycle arrest. In cancer cells, IkB is phosphorylated by IKK, PKD1 or p-PKCa, followed by the nuclear translocation of NF-kB and the activation of cyclin D1 genes regulated by NF-kB, which enhances the expression of cyclin D1 and its binding to CDK4/6, promoting the proliferation of cancer cells. PKD1 is phosphorylated entirely by p-PKCe. Results of studies using HCC cells revealed that VK2 could inhibit the function of IKK, the phosphorylation of PKCe and the catalytic action of activated PKCa, but not the phosphorylation of PKCa. This suppresses the aberrant activity of NF-kB and induces cell-cycle arrest in cancer cells. The cell-cycle regulatory proteins p27 and p21 are CDK inhibitors, acting to hinder cell-cycle progression. In HCC cells, VK2 increases the expression of P21 and then leads to cell cycle arrest. However, in leukemic cells, VK2 upregulates the expression p27 not p21 to induce cell cycle arrest. Besides, VK2 suppresses the high expression of HDGF in HCC cells and c-MYC in HL-60 leukemia cells at the transcriptional level, and then induces cell-cycle arrest. VK2 has been identified to stimulate the phosphorylation of PKA and activate AP-2, USF-1 and CREB transcriptional factors to inhibit the proliferation of HCC cells. At present, the activities of these transcriptional factors are potential downstream pathways of VK2 activation of PKA. In HCC cells, Cx43 expression is highly upregulated, which inhibits Cx32 expression. The VK2-dependent suppression of Cx43 expression at the transcriptional level enhances Cx32 activity, altering cancer cells differentiation. In addition, VK2 promotes differentiation of myeloid progenitors partly due to its binding to SXR and upregulation of transcriptional factors C/EBPa and PU.1 crucial for myeloid development. VK2 binding to SXR may subsequently improve the expression of C/EBPa and PU.1, which may elucidate the reason behind the therapeutic effect of VK2 on patients with MDS. NF-kB, nuclear factor-KB; IkB, inhibitor of NF-kB; Cdk, cyclin-dependent kinase; CREB, cAMP-response element binding protein; Cx, connexin; HCC, hepatocellular carcinoma; HDGF, hepatoma-derived growth factor; IKK, IkB kinase; MDS, myelodysplastic syndrome; p-PKA, phosphorylated protein kinase A; p-PKCa, phosphorylated PKCa; p-PKCe, phosphorylated PKCe; PKD1, protein kinase D1; p-PKD1, phosphorylated protein kinase D1; SXR, steroid and xenobiotic receptor; VK2, vitamin K2; AP-2, activating protein2; USF-1, upstream transcription factor; C/EBPa, CCAAT/enhancer-binding protein-a.

Figure 2. Cell apoptosis induced by VK2 in cancer cells. VK2 induces apoptosis in cancer cells by depolarizing the mitochondrial membrane potential, followed by cytochrome c release from the mitochondria into the cytosol to form apoptosomes, which then activates caspase-3. The precise mechanism of VK2-dependent initiation of the mitochondrial apoptosis pathway of cancer cells is as follows. In HL-60 leukemia cells, VK2 and VK2-O selectively binds to the mitochondrial protein Bak. VK2-induced ROS generation prior to the induction of apoptosis possibly contributes by converting VK2 to VK2-O. In myeloma cells, VK2 activates p38 MAPK to its phosphorylated form. VK2 exposure in PA-1 ovarian cancer cells may activate JNK to phosphorylate TR3, also known as Nur77 and neuron growth factor inducible factor I-B, and increase TR3 levels in the mitochondria. The hypothesis that the release of cytochrome c from the mitochondria partly results from the acidic phospholipid CL being peroxidated by ROS is yet to be confirmed. The role of ERK in the VK2‑dependent activation of caspase-3 and induction of apoptosis in hepatocellular carcinoma and pancreatic cancer cells is contradictory, so this pathway is represented with a dashed line. VK2 can inhibit ERK phosphorylation by suppressing the Ras activation and subsequently suppressing the catalysis of MEK, which causes apoptosis in HCC cells. Conversely, VK2-dependent induction of pancreatic cancer cell apoptosis is primarily associated with an increase in levels of phosphorylated ERK. In addition, VK2 stimulates the extrinsic apoptosis pathway by increasing p53 phosphorylation and then activating caspase-8 in Smmc-7721 HCC cells. Bak, Bcl-2 antagonist killer 1; Bcl-2, B-cell lymphoma 2; Bax, Bcl-2 associated X protein; CL, cardiolipin; HCC, hepatocellular carcinoma; VK2, vitamin K2; VK2-O, VK2-2,3 epoxide; ROS, reactive oxygen species; MAPK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; MEK, MAPK kinase; ERK, extracellular-signal-related kinase.

Despite the availability of multiple therapeutic methods for patients with cancer, the long-term prognosis is not satisfactory in a number of different cancer types. Vitamin K2 (VK2), which exerts anticancer effects on a number of cancer cell lines, is considered to be a prospective novel agent for the treatment of cancer. The present review aims to summarize the results of studies in which VK2 was administered either to patients with cancer or animals inoculated with cancerous cells, particularly investigating the inhibitory effects of VK2 on cancerous cells, primarily involving cell-cycle arrest, cell differentiation, apoptosis, autophagy and invasion. The present review summarizes evidence stating that treatment with VK2 could positively inhibit the growth of cancer cells, making it a potentially useful approach for the prevention and clinical treatment of cancer. Additionally, the combination treatment of VK2 and established chemotherapeutics may achieve better results, with fewer side effects. Therefore, more attention should be paid to the effects of micronutrients on tumors.

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