Vitamin K2 and its derivatives induce apoptosis in leukemia cells and enhance the effect of all-trans retinoic acid

Yaguchi, Makoto; Miyazawa, Kenji; Katagiri, Tatsuo; Nishimaki, Jiroh; Kizaki, Masahiro; Tohyama, Kaoru; Toyama, K

doi:10.1038/sj.leu.2400667

Cited by 76 publications

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“…13 We have recently reported that VK2 analogs such as menaquinone (MK)-3, MK-4 and MK-5, but not VK1, induce apoptosis in primary cultured leukemia cells including post-MDS AML cells in vitro. 7 This induction of apoptosis was more potent than that caused by equivalent concentrations of polyprenylalcohols. 7 The apoptosis inducing effect of VK2 was more pronounced in leukemic blasts than in mature nonblastic cells as shown by flow cytometric analysis using the apoptosis-specific antibody APO2.7.…”

Section: Introductionmentioning

confidence: 93%

“…7 This induction of apoptosis was more potent than that caused by equivalent concentrations of polyprenylalcohols. 7 The apoptosis inducing effect of VK2 was more pronounced in leukemic blasts than in mature nonblastic cells as shown by flow cytometric analysis using the apoptosis-specific antibody APO2.7. 7,14,15 These results were obtained on mononuclear cells from whole bone marrow of patients with RAEB-T (refractory anemia with excess of blasts in transformation) whose bone marrow contains less than 30% blast cells.…”

Section: Introductionmentioning

confidence: 93%

“…7,16 We also investigated the effects of VK2 on the MDS-KZ cell line. As shown in Figure 3, a 72 h exposure to MK5 resulted in inhibition of cell growth in a dose-dependent manner (IC 50 : 5 M).…”

Section: Vk2 Induces Apoptosis In the Mds-kz Cell Linementioning

confidence: 99%

“…7 The apoptosis inducing effect of VK2 was more pronounced in leukemic blasts than in mature nonblastic cells as shown by flow cytometric analysis using the apoptosis-specific antibody APO2.7. 7,14,15 These results were obtained on mononuclear cells from whole bone marrow of patients with RAEB-T (refractory anemia with excess of blasts in transformation) whose bone marrow contains less than 30% blast cells. 16 Oral administration of VK2 (MK4) to a patient with MDS and myelofibrosis resulted in a reduction of the number of peripheral leukemic blast cells and hematological improvement of anemia and thrombocytopenia without any toxicity.…”

Section: Introductionmentioning

confidence: 98%

“…The structures of VK1, VK2 and VK3 are described in more detail elsewhere. 6,7 Several lines of evidence are beginning to emerge showing that these congeners have some growth inhibitory effects on hepatoma cell lines such as Hep3B and Hep40, although the mechanisms of growth inhibition are not well understood. [8][9][10][11][12] In addition, geranylgeraniol, a polyprenylalcohol composing the side chain of VK2, was previously reported to be a potent inducer of apoptosis in tumor cell lines.…”

Section: Introductionmentioning

confidence: 99%

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1999

Leukemia

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 93%

Section: Vk2 Induces Apoptosis In the Mds-kz Cell Linementioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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1999

Leukemia

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Vitamin K and rheumatoid arthritis

Okamoto

2008

IUBMB Life

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SummaryVitamin K2 [menaquinone-4 (MK-4)] has been reported to induce apoptosis in hepatocellular carcinoma, leukemia, and MDS cell lines. The effects of MK-4 on the development of arthritis have never been addressed so far. In this study, we investigated the effect of MK-4 upon the proliferation of rheumatoid synovial cells and the development of arthritis in collageninduced arthritis (CIA). We analyzed the effect of MK-4 on the proliferation of fibroblast-like synoviocytes (FLSs) using the 3-(4,5-demethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The proapoptotic effect of MK-4 upon FLS was investigated with annexin V staining and DNA fragmentation and caspase 3/7 assays. Moreover, we analyzed the effect of MK-4 on the development of CIA in female dark agouti rats. Our results indicated that MK-4 inhibited the proliferation of FLS and the development of CIA in a dose-dependent manner. We concluded that MK-4 may represent a new agent for the treatment of RA in the setting of combination therapy with other disease-modifying antirheumatic drugs. Keywords vitamin K2 (menaquinone-4); rheumatoid arthritis; apoptosis; collagen type II-induced arthritis.

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K vitamins, PTP antagonism, and cell growth arrest

Carr

Wang

Kar

2002

Journal Cellular Physiology

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The main function of K vitamins is to act as co-factors for g-glutamyl carboxylase. However, they have also recently been shown to inhibit cell growth. We have chemically synthesized a series of K vitamin analogs with various side chains at the 2 or 3 position of the core naphthoquinone structure. The analogs with short thio-ethanol side chains are found to be more potent growth inhibitors in vitro of various tumor cell lines. Cpd 5 or [2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone] is one of the most potent. The anti-proliferation activity of these compounds is antagonized by exogenous thiols but not by non-thiol antioxidants. This suggests that the growth inhibition is mediated by sulfhydryl arylation of cellular glutathione and cysteine-containing proteins and not by oxidative stress. The protein tyrosine phosphatases (PTP) are an important group of proteins that contain cysteine at their catalytic site. PTPs regulate mitogenic signal transduction and cell cycle progression. PTP inhibition by Cpd 5 results in prolonged tyrosine phosphorylation and activation of several kinases and transcription factors including EGFR, ERK1/2, and Elk1. Cpd 5 could activate ERK1/2 either by signaling from an activated EGFR, which is upstream in the signaling cascade, or by direct inhibition of ERK1/2 phosphatase(s). Prolonged ERK1/2 phosphorylation strongly correlates with Cpd 5-mediated growth inhibition. Cpd 5 can also bind to and inhibit the Cdc25 family of dual specific phosphatases. As a result, several Cdc25 substrates (Cdk1, Cdk2, Cdk4) involved in cell cycle progression are tyrosine phosphorylated and thereby inhibited by its action. Cpd 5 could also inhibit both normal liver regeneration and hepatoma growth in vivo. DNA synthesis during rat liver regeneration following partial hepatectomy, transplantable rat hepatoma cell growth, and glutathione-S-transferase-pi expressing hepatocytes after administration of the chemical carcinogen diethylnitrosamine, are all inhibited by Cpd 5 administration. The growth inhibitory effect during liver regeneration and transplantable tumor growth is also correlated with ERK1/2 phosphorylation induced by Cpd 5. Thus, Cpd 5-mediated inhibition of PTPs, such as Cdc25 leads to cell growth arrest due to altered activity of key cellular kinases involved in signal transduction and cell cycle progression. This prototype K vitamin analog represents a novel class of growth inhibitor based upon its action as a selective PTP antagonist. It is clearly associated with prolonged ERK1/2 phosphorylation, which is in contrast with the transient ERK1/2 phosphorylation induced by growth stimulatory mitogens.

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Vitamin K2 and its derivatives induce apoptosis in leukemia cells and enhance the effect of all-trans retinoic acid

Cited by 76 publications

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Vitamin K and rheumatoid arthritis

K vitamins, PTP antagonism, and cell growth arrest

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