Apoptosis/differentiation-inducing effects of vitamin K2 on HL-60 cells: dichotomous nature of vitamin K2 in leukemia cells

Miyazawa, Kenji; Yaguchi, Makoto; Funato, K; Gotoh, Akihiko; Kawanishi, Yasuo; Nishizawa, Yuji; Yuo, Akira; Ohyashiki, Kazuma

doi:10.1038/sj.leu.2402155

Cited by 58 publications

(73 citation statements)

References 42 publications

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“…4,10 Therefore, we first examined growth inhibition and apoptosis induction of HL-60 cells after treatment with VK2 and OCT. Flow cytometry revealed that treatment with VK2 activates caspase-3 activity and induces apoptosis in HL-60 cells as previously reported (Figure 2). 10 In the presence of 10 nM of OCT alone, no caspase-3 activity and apoptosis induction was observed, and rather suppressed spontaneous caspase-3 activation of HL-60 cells cultured in control medium containing 10% FCS. Notably, by the combined treatment with VK2 plus OCT, VK2-induced caspase-3 activation and apoptosis induction was significantly suppressed.…”

Section: Combination Of Vk2 Plus Oct Suppressed Vk2-induced Apoptosismentioning

confidence: 90%

“…9 Recently, we observed that VK2 treatment induced monocytic differentiation in HL-60-bcl-2 cells, which enforced overexpression of BCL-2 by gene transfection, whereas VK2 induced apoptosis in HL-60-neo cells. 10 It is noteworthy that although HL-60-bcl-2 became almost completely resistant to apoptosis induction by VK2, monocytic differentiation via G0/G1 arrest was still observed. 10 This suggests that VK2 promotes not only apoptosis induction but also a differentiation-inducing effect against the leukemia cells, which are resistant to VK2-inducing apoptosis.…”

Section: Introductionmentioning

confidence: 96%

“…10 It is noteworthy that although HL-60-bcl-2 became almost completely resistant to apoptosis induction by VK2, monocytic differentiation via G0/G1 arrest was still observed. 10 This suggests that VK2 promotes not only apoptosis induction but also a differentiation-inducing effect against the leukemia cells, which are resistant to VK2-inducing apoptosis. It has been well documented that VD3 is capable of inhibiting proliferation and inducing differentiation of leukemic myeloid cells into the monocyte/macrophage lineage.…”

Section: Introductionmentioning

confidence: 96%

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Combination of 22-oxa-1,25-dihydroxyvitamin D3, a vitamin D3 derivative, with vitamin K2 (VK2) synergistically enhances cell differentiation but suppresses VK2-inducing apoptosis in HL-60 cells

et al. 2002

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Section: Combination Of Vk2 Plus Oct Suppressed Vk2-induced Apoptosismentioning

confidence: 90%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 96%

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Combination of 22-oxa-1,25-dihydroxyvitamin D3, a vitamin D3 derivative, with vitamin K2 (VK2) synergistically enhances cell differentiation but suppresses VK2-inducing apoptosis in HL-60 cells

et al. 2002

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“…Overexpression of BCL-2 in tumors critically alters this balance and results in the permanent survival of tumors. It has also been reported that overexpression of BCL-2 in a leukemia cell line resulted in resistance against VK2-induced apoptosis, however, these cells still underwent differentiation via G1 arrest (18). Thus, downregulation of BCL-2 may restore this balance and further increase the ability of tumor cells to respond to the apoptotic signal induced by exogenous stimuli (19).…”

Section: Discussionmentioning

confidence: 95%

Enhanced therapeutic efficacy of vitamin K2 by silencing BCL-2 expression in SMMC-7721 hepatocellular carcinoma cells

et al. 2012

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Abstract. Vitamin K2 (VK2) exerts cell growth inhibitory effects in various human cancer cells such as SMMC-7721 hepatocellular carcinoma (HCC) cells. BCL-2 is an antiapoptotic protein that is frequently overexpressed in numerous tumors. Modulation of multiple antiapoptotic signaling pathways involving BCL-2, which are related to growth factor-stimulated signal transduction in cell survival, is essential for enhancement of the cytotoxic effect of anticancer drugs. In this study, we tested a new strategy of gene therapy by combining BCL-2 siRNA with VK2. In SMMC-7721 HCC cells, the combined treatment significantly enhanced cytotoxicity compared with treatment with either VK2 or siBCL-2 alone. We found that combined treatment induced a significantly different level of G2 stage inhibition. Furthermore, the p53 protein was overexpressed 24 h subsequent to combination treatment, and p21 was clearly increased at 36 h as a consequence of the increased p53 activity. In conclusion, these data suggest that the antitumor effect of VK2 may be improved by silencing BCL-2 expression in SMMC-7721 HCC cells and provides support for the combined use of VK2 and siBCL-2 as a promising approach in cancer gene therapy.

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“…We also found that vitamin K1 could weakly inhibit cell growth both in vitro and possibly in human HCC patients (Carr BI, 1996). Others have also found that K vitamins have some inhibitory action on cell growth in vitro Lamson and Plaza, 2003;Yoshiji et al, 2005;Yokoyama et al, 2005;Oztopcu et al, 2004;Shibayama et al, 2003;Miyazawa et al, 2001;Sun et al, 2000;Taper et al, 2004). The mechanism(s) for the weak growth inhibitory actions of natural K vitamins have not been identified.…”

Section: Discussionmentioning

confidence: 99%

Growth inhibitory actions of prothrombin on normal hepatocytes: Influence of matrix

Carr

Kar

Wang

et al. 2007

Cell Biology International

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Most hepatomas have a defect in prothrombin carboxylation, and can secrete under-carboxylated prothrombin or des-γ-carboxy-prothrombin (DCP), the function of which is unknown. We considered that prothrombin-DCP axis might also be involved in growth control. Hepatocytes and hepatoma cells were treated with prothrombin, and DNA synthesis and cytoskeleton were studied. Prothrombin inhibited DNA synthesis in hepatocytes on fibronectin, but not collagen matrix. Hepatoma cell lines were not inhibited. We found that hepatoma cell matrix conferred resistance to hepatocytes. Prothrombin decreased fibronectin but not collagen amounts, but only in the presence of hepatocytes and not hepatoma cells, indicating that it has a differential action on matrix proteins. It also caused changes in cell shape and actin depolymerization. In vivo, there was a decrease in plasma prothrombin activity after a partial hepatectomy (PH) concomitant with a peak of DNA synthesis by the hepatocyte at 24 h after PH. Injection of warfarin at the time of PH, further inhibited PT activity and enhanced this 24 h peak of DNA synthesis. Furthermore, repeated injection of prothrombin lowered the peak DNA synthesis after PH. The data support the hypothesis that prothrombin can act as a hepatocyte growth inhibitor, likely at the level of fibronectin loss and result in cytoskeletal changes. Hepatomas resist this action, possibly due to their different matrix proteins. This represents a novel mechanism for growth regulation and provides a possible biological significance for the tumor marker DCP.

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Apoptosis/differentiation-inducing effects of vitamin K2 on HL-60 cells: dichotomous nature of vitamin K2 in leukemia cells

Cited by 58 publications

References 42 publications

Combination of 22-oxa-1,25-dihydroxyvitamin D3, a vitamin D3 derivative, with vitamin K2 (VK2) synergistically enhances cell differentiation but suppresses VK2-inducing apoptosis in HL-60 cells

Combination of 22-oxa-1,25-dihydroxyvitamin D3, a vitamin D3 derivative, with vitamin K2 (VK2) synergistically enhances cell differentiation but suppresses VK2-inducing apoptosis in HL-60 cells

Enhanced therapeutic efficacy of vitamin K2 by silencing BCL-2 expression in SMMC-7721 hepatocellular carcinoma cells

Growth inhibitory actions of prothrombin on normal hepatocytes: Influence of matrix

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