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Takeda K.,University of Ryukyus | Takeda K.,Kanehide Bio Co. | Tomimori K.,University of Ryukyus | Tomimori K.,Naha City Hospital | And 6 more authors.
International Journal of Oncology | Year: 2012

Fucoidan, a sulfated polysaccharide, has significant cytotoxic activity against tumor cells; however, the mechanism(s) of this action remains poorly understood. The present study was designed to determine the in vitro and in vivo effects of fucoidan and their molecular mechanisms. Fucoidan from Cladosiphon okamuranus Tokida cultivated in Okinawa, Japan, delayed tumor growth in Sarcoma 180 (S-180)-bearing mice. However, it failed to inhibit S-180 cell growth in vitro. Activated macrophages are known to have anti-tumor effects. Murine RAW264.7 macrophages stimulated with fucoidan exerted cytotoxicity towards S-180 cells in vitro. This cytotoxicity was associated with nitric oxide (NO) production. Both cytocidal effect and NO production were significantly inhibited by L-NAME, an inhibitor of NO synthase (NOS). Furthermore, activation of nuclear factor-κB was a key step in the transcriptional activation of the inducible NOS gene. Taken together, our results indicate that the anti-tumor activity of fucoidan on S-180 cells is mediated through increased NO production by fucoidan-stimulated macrophages via nuclear factor-κB-dependent signaling pathway.


Tomimori K.,University of Ryukyus | Tomimori K.,Naha City Hospital | Nakama S.,University of Ryukyus | Nakama S.,Musashino Research Institute for Immunity | And 6 more authors.
BMC Complementary and Alternative Medicine | Year: 2012

Background: Crassocephalum crepidioides, a plant distributed in Okinawa Islands, is known in folk medicine; however, its anticancer activity has not been investigated. The aim of this study was to determine the in vitro and in vivo antitumor activities of C. crepidioides on murine Sarcoma 180 (S-180) and related molecular mechanisms. Methods: The antitumor effect of C. crepidioides was evaluated in S-180-cell-bearing mice. Cell growth was assessed using a colorimetric assay. Nitrite and nitrate levels were measured by colorimetry. The expression levels of inducible NO synthase (iNOS) in murine RAW264.7 macrophages was assessed by reverse transcriptase-polymerase chain reaction. Activation of iNOS promoter was detected by reporter gene. Activation of nuclear factor-κB (NF-κB) was evaluated by electrophoretic mobility shift assay. The role of NF-κB signaling was analyzed using inhibitors of NF-κB and dominant-negative mutants, and Western blot analysis.Results: C. crepidioides extract delayed tumor growth in S-180-bearing mice. However, it did not inhibit S-180 cell growth in vitro. Supernatant of cultured C. crepidioides-stimulated RAW264.7 macrophages was cytotoxic to S-180 cells. This cytotoxicity was associated with nitric oxide (NO) production. NF-κB signaling pathway was crucial for the transcriptional activation of iNOS gene. Isochlorogenic acid, a component of C. crepidioides, induced NF-κB activation and iNOS expression.Conclusions: The results highlight the oncolytic and immunopotentiation properties of C. crepidioides mediated through NF-κB-induced release of NO from macrophages. © 2012 Tomimori et al.; licensee BioMed Central Ltd.


Tsumuraya T.,University of Ryukyus | Ishikawa C.,University of Ryukyus | Ishikawa C.,Transdisciplinary Research Organization for Subtropics and Island Studies | MacHijima Y.,University of Ryukyus | And 4 more authors.
Biochemical Pharmacology | Year: 2011

We evaluated the anti-adult T-cell leukemia (ATL) effects of hippuristanol, an eukaryotic translation initiation inhibitor from the coral Isis hippuris. Hippuristanol inhibited proliferation of HTLV-1-infected T-cell lines and ATL cells, but not normal peripheral blood mononuclear cells. It induced cell cycle arrest during G1 phase by reducing the expression of cyclin D1, cyclin D2, CDK4 and CDK6, and induced apoptosis by reducing the expression of Bcl-xL, c-IAP2, XIAP and c-FLIP. The induced apoptosis was associated with activation of caspase-3, -8 and -9. Hippuristanol also suppressed IkappaBalpha phosphorylation and depleted IKKalpha, IKKgamma, JunB and JunD, resulting in inactivation of NF-kappaB and AP-1. It also suppressed carbonic anhydrase type II expression. In addition to its in vitro effects, hippuristanol suppressed tumor growth in mice with severe combined immunodeficiency harboring tumors induced by inoculation of HTLV-1-infected T cells. These preclinical data suggest that hippuristanol could be a potentially useful therapeutic agent for patients with ATL. © 2011 Elsevier Inc.


Yamamoto K.,University of Ryukyus | Ishikawa C.,University of Ryukyus | Ishikawa C.,Transdisciplinary Research Organization for Subtropics and Island Studies | Katano H.,Japan National Institute of Infectious Diseases | And 2 more authors.
Cancer Letters | Year: 2011

Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin's lymphoma caused by human herpesvirus 8. Conventional chemotherapy has limited effect on PEL, and the prognosis is poor. Carotenoids are a family of natural pigments and have several biological functions. We evaluated the anti-PEL effects of carotenoid, fucoxanthin (FX) and its metabolite, fucoxanthinol (FXOH). Treatment of PEL cells with FX or FXOH induced cell cycle arrest during G1 phase and caspase-dependent apoptosis. FX and FXOH treatment silenced NF-κB, AP-1 and Akt activation, in conjunction with down-regulation of anti-apoptotic proteins and cell cycle regulators. Importantly, proteasome degradation was responsible for the low levels of proteins after FXOH treatment. In animal studies, treatment with FX reduced the growth of PEL-cell tumors. The results provide the rationale for future clinical use of FX and FXOH for the treatment of PEL. © 2010 Elsevier Ireland Ltd.


Tafuku S.,University of Ryukyus | Ishikawa C.,University of Ryukyus | Ishikawa C.,Transdisciplinary Research Organization for Subtropics and Island Studies | Yasumoto T.,Okinawa Institute of Science and Technology | Mori N.,University of Ryukyus
Oncology Reports | Year: 2012

Fucoxanthin (FX) is a natural carotenoid with reported antitumorigenic activity. This study explored the effects of FX and its deacetylated product, fucoxanthinol (FXOH), on B-cell malignancies, including Burkitt's lymphoma, Hodgkin's lymphoma and Epstein-Barr virus-immortalized B cells. Both FX and FXOH reduced the viability of these malignant B cells in a dose-dependent manner accompanied by the induction of cell cycle arrest during G1 phase and caspase-dependent apoptosis. FXOH was approximately twice more potent than FX in these activities. In contrast, normal peripheral blood mononuclear cells were resistant to FX and FXOH. Strong and constitutive activation of nuclear factor-κB (NF-κB) is a common characteristic of many B-cell malignancies, and FXOH suppressed constitutive NF-κB activity. NF-κB inhibition was accompanied by downregulation of NF-κB-dependent anti-apoptotic and cell cycle regulator gene products, including Bcl-2, cIAP-2, XIAP, cyclin D1 and cyclin D2. The results indicated that FX and FXOH are potentially useful therapeutic agents in B-cell malignancies characterized by aberrant regulation of NF-κB.


Ishikawa C.,University of Ryukyus | Ishikawa C.,Transdisciplinary Research Organization for Subtropics and Island Studies | Mori N.,University of Ryukyus
International Journal of Oncology | Year: 2013

Latent membrane protein 1 (LMP-1) of Epstein Barr virus (EBV) promotes tumorigenesis. Here, we report that LMP-1 activates the immunoregulatory molecule CD69 gene transcription through a nuclear factor-κB (NF-κB) dependent pathway. CD69 expression was upregulated in LMP-1 expressing EBV-immortalized human B-cell lines and an EBV-positive Burkitt's lymphoma cell line. LMP-1 expression increased CD69 expression at the transcriptional level. CD69 promoter was regulated by LMP-1 activation of NF-κB via the carboxy-terminal activation region 1 and 2. Promoter deletion analysis indicated that two NF-κB binding sites are necessary for activation of the CD69 promoter. Electrophoretic mobility shift analysis demonstrated that LMP-1 activates both NF-κB binding sites in the CD69 promoter. This is the first report of the regulation of CD69 expression by LMP-1, and this novel finding may, thus, represent an important link between the EBV oncoprotein LMP-1 and its critical role in the development of EBV-associated diseases.


Ishikawa C.,University of Ryukyus | Ishikawa C.,Transdisciplinary Research Organization for Subtropics and Island Studies | Jomori T.,University of Ryukyus | Tanaka J.,University of Ryukyus | And 2 more authors.
International Journal of Oncology | Year: 2016

Human T-cell leukemia virus type 1 (HTLV-1) causes either adult T-cell leukemia (ATL) or chronic inflammatory disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis. These diseases are not curable as yet; therefore new agents for treatment and prevention are needed. Carotenoids are natural plant compounds with anti-carcinogenic activities. Peridinin is one of the most abundant carotenoids found in nature. Based on a series of past experiments, here we investigated the effects of peridinin extracted from Okinawan coral Isis hippuris on the proliferation and survival of HTLV-1-infected T-cell lines. The results of water-soluble tetrazolium-8 assay indicated that peridinin dose-dependently inhibits cell proliferation and viability of HTLV-1-infected T-cell lines. Flow cytometry showed that low concentration of peridinin induced cell cycle arrest at G1 phase, while higher concentration induced apoptosis. Peridinin caused cleavage of caspase-3, -8 and -9. Peridinin significantly reduced the expression of G1 cell cycle regulators, including cyclin D1, cyclin D2, CDK4, CDK6 and c-Myc, and anti-apoptotic proteins, including survivin, XIAP and Bcl-2, in a dose-dependent manner. Peridinin suppressed DNA binding of NF-B. Peridinin inhibited phosphorylation of IBα, RelA, Akt and p70 S6 kinase, and reduced protein expression level of 3-phosphoinositide-dependent protein kinase 1. Thus, peridinin exerts its anti-proliferative and pro-apoptotic effects by suppressing NF-B and Akt signaling in HTLV-1-infected T cells. Peridinin also reduced tumor growth in mice harboring ATL xenograft tumors. The results suggested that peridinin is a potentially suitable therapeutic agent against HTLV-1- associated diseases.

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