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

Funato, K; Miyazawa, Kenji; Yaguchi, Makoto; Gotoh, Akihiko; Ohyashiki, Kazuma

doi:10.1038/sj.leu.2402614

Cited by 24 publications

(24 citation statements)

References 39 publications

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“…The possible role of Vit D in the regulation of immune responses is strongly supported by the findings that almost all immune cells, including T cells, B cells, monocytes, neutrophils, platelets, macrophages, and dendritic cells express Vit D receptors and that Vit D appears to modulate the activity of these cells (Hewison, 2011). The ligand for VDR also showed a synergic activity with Vitamin A, Vitamin K2, and certain chemotherapeutic agents (Funato et al, 2002;James et al, 1999). Interestingly, only naive T cells display very low VDR levels, while this receptor is abundantly present upon T cell activation (Hewison, 2011).…”

Section: Vit D and The Immune Systemmentioning

confidence: 64%

“…Maxacalcitol (22-oxa-1a,25-D3) Maxacalcitol (1a,25-dihydroxy-22-oxacalcitriol) (OCT) (Figure 2) is another non-calcemic Vit D analogue and VDR ligand that has been shown to promote cell differentiation and to inhibit cell proliferation, without inducing hypercalcemia (Abe et al, 1991;Nishii & Okano, 2001;Funato et al, 2002). This molecule contains an oxygen in place of a carbon in position 22 of the side chain (Figure 2) and is less calcemic than 1,25(OH) 2 D 3 .…”

Section: Calcipotriolmentioning

confidence: 99%

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Vitamin D in cancer chemoprevention

Giammanco¹,

Majo²,

Guardia

et al. 2015

Pharmaceutical Biology

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Context: There is increasing evidence that Vitamin D (Vit D) and its metabolites, besides their well-known calcium-related functions, may also exert antiproliferative, pro-differentiating, and immune modulatory effects on tumor cells in vitro and may also delay tumor growth in vivo. Objective: The aim of this review is to provide fresh insight into the most recent advances on the role of Vit D and its analogues as chemopreventive drugs in cancer therapy. Methods: A systematic review of experimental and clinical studies on Vit D and cancer was undertaken by using the major electronic health database including ISI Web of Science, Medline, PubMed, Scopus and Google Scholar. Results and conclusion: Experimental and clinical observations suggest that Vit D and its analogues may be effective in preventing the malignant transformation and/or the progression of various types of human tumors including breast cancer, prostate cancer, colorectal cancer, and some hematological malignances. These findings suggest the possibility of the clinical use of these molecules as novel potential chemopreventive and anticancer agents.

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Section: Vit D and The Immune Systemmentioning

confidence: 64%

Section: Calcipotriolmentioning

confidence: 99%

Vitamin D in cancer chemoprevention

Giammanco¹,

Majo²,

Guardia

et al. 2015

Pharmaceutical Biology

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“…It has been shown that the combination therapy of vitamin K2 with a vitamin D3 derivate synergistically enhanced the differentiation of leukemia cells in vitro (46). The combination of vitamin K3 with vitamin C was shown to induce synergistic antitumor activity on ovarian cancer cells in vitro (47).…”

Section: Discussionmentioning

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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“…VK2 has been reported to show anticancer effects inducing apoptosis and cell cycle arrest in several tumor cell types such as leukemia cells, osteosarcoma cells, HCC cells, glioma cells, and lung cancer cells, also a number of striking anecdotal clinical reports supports use of VK2 as an anticancer agent (7)(8)(9)(10)(11)(12)(13)22). However, therapies combining VK2 with established anti-tumor agents have not been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…VK2 has been found to inhibit in vitro and in vivo growth of cancer cells including glioma, lung cancer, leukemia, and HCC cells (7)(8)(9)(10). Cell cycle arrest and apoptosis are believed to be involved in this action of VK2, but precise molecular mechanisms underlying VK2-induced growth inhibition and killing in HCC cells remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Vitamin K2 augments 5-fluorouracil-induced growth inhibition of human hepatocellular carcinoma cells by inhibiting NF-κB activation

Zhang

Ozaki²,

Hamajima³

et al. 2010

Oncol Rep

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Abstract.Although 5-fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents in various cancer including hepatocellular carcinoma (HCC), chemoresistance has precluded single use of 5-FU in clinical settings. Since menatetrenone, an analogue of vitamin K2 (VK2), inhibits growth of cancer cells including HCC cells in vitro and in vivo, we examined VK2 modulation of HCC cell response to 5-FU. VK2 pretreatment dose-dependently enhanced growth-inhibition by 5-FU through a G1 cell cycle arrest. VK2 inhibited 5-FU-induced NF-κB activation and cyclin D1 expression. Therefore, combination of VK2 and 5-FU might represent a new therapeutic strategy for patients with HCC.

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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

Cited by 24 publications

References 39 publications

Vitamin D in cancer chemoprevention

Vitamin D in cancer chemoprevention

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

Vitamin K2 augments 5-fluorouracil-induced growth inhibition of human hepatocellular carcinoma cells by inhibiting NF-κB activation

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