Vitamin K2 induces apoptosis of a novel cell line established from a patient with myelodysplastic syndrome in blastic transformation

Nishimaki, Jiroh; Miyazawa, Kenji; Yaguchi, Makoto; Katagiri, Tomoko; Kawanishi, Yasuo; Toyama, Keisuke; Ohyashiki, Kazuma; Hashimoto, Sachiko; Nakaya, Kazuyasu; Takiguchi, Tomoo

doi:10.1038/sj.leu.2401491

Cited by 33 publications

(23 citation statements)

References 10 publications

(15 reference statements)

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“…However, the signaling pathways leading to mitochondria have not been elucidated, though we have previously reported that treatment with an MDS cell line with VK2 induced up-regulation of BAX and down-regulation of BCL-2 protein expressions. 11 It was proposed that the nuclear binding protein for vitamin K2 exists in nuclei similar to other vitamin receptors and that the molecular structure is very close to that of human GAPDH. 38 However, so far, the specific receptor for VK2 is still not yet identified.…”

Section: Discussionmentioning

confidence: 99%

“…3 In addition, up-modulation of BAX and downmodulation of BCL-2 expressions were observed in a VK2-treated MDS-KZ cell line, a MDS cell line which undergoes apoptosis in response to VK2. 11 Although VK1 and VK2 share the naphthoquinone nucleus, only VK2 causes programmed cell death. 3 Therefore, both a polyprenylalcohol and a naphthoquinone nucleus may thus be required for maximal apoptotic efficacy.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2001

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2001

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“…It has been shown that vitamins K1, K2 and K3 could inhibit the growth of various rodent-and human-derived neoplastic cell lines in vitro, such as oral epidermal cancer, nasopharyngeal cancer, breast cancer, leukemia and hepatocellular carcinoma (HCC) cell lines (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). In marked contrast to numerous reports demonstrating in vitro antitumor effects of vitamin K, there are few reports demonstrating in vivo antitumor effects of vitamin K. Furthermore, it has not been examined so far whether vitamin K induces antitumor effects on CRC.…”

Section: Introductionmentioning

confidence: 99%

Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells

Ogawa¹,

Nakai²,

Deguchi³

et al. 2007

Int J Oncol

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Abstract. Although a number of studies have shown that vitamin K possesses antitumor activities on various neoplastic cell lines, there are few reports demonstrating in vivo antitumor effects of vitamin K, and the antitumor effect on colorectal cancer (CRC) remains to be examined. Therefore, antitumor effects of vitamin K on CRC were examined both in vitro and in vivo. Vitamins K2, K3 and K5 suppressed the proliferation of colon 26 cells in a dose-dependent manner, while vitamin K1 did not. On flow cytometry, induction of apoptosis by vitamins K2, K3 and K5 was suggested by population in sub-G1 phase of the cell cycle. Hoechst 33342 staining and a twocolor flow cytometric assay using fluorescein isothiocyanateconjugated annexin V and propidium iodide confirmed that vitamins K2, K3 and K5 induced apoptotic death of colon 26 cells. Enzymatic activity of caspase-3 in colon 26 cells was significantly up-regulated by vitamins K2, K3 and K5. The pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Aspfluoromethyl ketone, substantially prevented vitamin Kmediated apoptosis. In vivo study using syngeneic mice with subcutaneously established colon 26 tumors demonstrated that intravenous administration of vitamins K2, K3 and K5 significantly suppressed the tumor growth. The number of apoptotic tumor cells was significantly larger in the vitamin K-treated groups than in the control group. These results suggest that vitamins K2, K3 and K5 exerted effective antitumor effects on CRC in vitro and in vivo by inducing caspasedependent apoptotic death of tumor cells, suggesting that these K vitamins may be promising agents for the treatment of patients with CRC. IntroductionWorldwide, colorectal cancer (CRC) ranks third in cancer incidence after lung and breast, and is a major cause of cancer mortality (1). In 2000, there were 943,000 new cases diagnosed and 510,000 deaths worldwide, corresponding figures for Europe were 363,000 cases and 199,000 deaths (2). Although surgery alone is the standard approach in localized malignancy, approximately 50% of early-stage patients present disease relapse (3). Furthermore, approximately 30% of CRC is diagnosed when it is already at an advanced stage. There are also a considerable number of patients who cannot undergo surgery even at an early stage of the disease due to severe complications, such as chronic heart failure, chronic renal failure and chronic obstructive pulmonary diseases. Fluoropyrimidine-based chemotherapy is now considered the standard treatment for patients with inoperable CRC, but approximately 90% of patients do not respond to chemotherapy based on 5-fluorouracil (5-FU)/folinic acid (4). Thus, the development of new treatment modalities is necessary to improve the overall survival rate of patients with CRC.Vitamin K is an essential vitamin that was discovered as a fat-soluble anti-hemorrhagic agent. Vitamin K is also known as an obligatory cofactor in the post-translational γ-carboxylation of glutamic acid residues (5-8). Vitamin K-dependent proteins include prothrombin (fact...

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“…The incidence of apoptosis was determined by flow cytometric analysis with an FITCconjugated APO2.7 monoclonal antibody (clone 2.7), which was raised against the 38 kDa mitochondrial membrane protein (7A6 antigen) expressed by cells undergoing apoptosis. 7 Incubation with up to 10 M STI571 for 48 h did not result in increased apoptosis among parental TF-1 cells in the presence of GM-CSF (100 U/ml). Further, even though the incubation of TF-1 BCR-ABL cells with STI571 at a concentration of either 1 M or 10 M induced apoptosis in the absence of GM-CSF, the addition of GM-CSF abated the apoptotic effects of STI571 in these cells ( Figure 1b).…”

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confidence: 84%

Relationship between methylation of the p15 gene in myelodysplastic syndromes (MDS)

et al. 2001

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Vitamin K2 induces apoptosis of a novel cell line established from a patient with myelodysplastic syndrome in blastic transformation

Abstract: We have previously reported that vitamin K 2 (VK2) has a potent apoptosis inducing activity toward various types of primary cultured leukemia cells including acute myelogenous leukemia arising from myelodysplastic syndromes (MDS). We estab-

Cited by 33 publications

References 10 publications

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

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

Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells

Relationship between methylation of the p15 gene in myelodysplastic syndromes (MDS)

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