Antiadult T-cell leukemia effects of brown algae fucoxanthin and its deacetylated product, fucoxanthinol
Chie Ishikawa
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Division of Child Health and Welfare, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
The Japanese Society for the Promotion of Science (JSPS), Tokyo, Japan
Search for more papers by this authorSenji Tafuku
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Tropical Technology Center Ltd, Uruma, Okinawa, Japan
Search for more papers by this authorTakashi Kadekaru
Tropical Technology Center Ltd, Uruma, Okinawa, Japan
Search for more papers by this authorShigeki Sawada
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Division of Oral and Maxillofacial Functional Rehabilitation, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Search for more papers by this authorMariko Tomita
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Search for more papers by this authorTaeko Okudaira
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Division of Endocrinology and Metabolism, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Search for more papers by this authorTetsuro Nakazato
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Division of Endocrinology and Metabolism, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Search for more papers by this authorTakayoshi Toda
Division of Laboratory Medicine, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Search for more papers by this authorJun-Nosuke Uchihara
Department of Internal Medicine, Naha City Hospital, Naha, Okinawa, Japan
Search for more papers by this authorNaoya Taira
Department of Internal Medicine, Heartlife Hospital, Nakagusuku, Okinawa, Japan
Search for more papers by this authorKazuiku Ohshiro
Department of Internal Medicine, Okinawa Prefectural Nanbu Medical Center and Children's Medical Center, Haebaru, Okinawa, Japan
Search for more papers by this authorTakeshi Yasumoto
Tropical Technology Center Ltd, Uruma, Okinawa, Japan
Search for more papers by this authorTakao Ohta
Division of Child Health and Welfare, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Search for more papers by this authorCorresponding Author
Naoki Mori
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Fax: +81-98-895-1410.
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, JapanSearch for more papers by this authorChie Ishikawa
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Division of Child Health and Welfare, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
The Japanese Society for the Promotion of Science (JSPS), Tokyo, Japan
Search for more papers by this authorSenji Tafuku
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Tropical Technology Center Ltd, Uruma, Okinawa, Japan
Search for more papers by this authorTakashi Kadekaru
Tropical Technology Center Ltd, Uruma, Okinawa, Japan
Search for more papers by this authorShigeki Sawada
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Division of Oral and Maxillofacial Functional Rehabilitation, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Search for more papers by this authorMariko Tomita
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Search for more papers by this authorTaeko Okudaira
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Division of Endocrinology and Metabolism, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Search for more papers by this authorTetsuro Nakazato
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Division of Endocrinology and Metabolism, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Search for more papers by this authorTakayoshi Toda
Division of Laboratory Medicine, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Search for more papers by this authorJun-Nosuke Uchihara
Department of Internal Medicine, Naha City Hospital, Naha, Okinawa, Japan
Search for more papers by this authorNaoya Taira
Department of Internal Medicine, Heartlife Hospital, Nakagusuku, Okinawa, Japan
Search for more papers by this authorKazuiku Ohshiro
Department of Internal Medicine, Okinawa Prefectural Nanbu Medical Center and Children's Medical Center, Haebaru, Okinawa, Japan
Search for more papers by this authorTakeshi Yasumoto
Tropical Technology Center Ltd, Uruma, Okinawa, Japan
Search for more papers by this authorTakao Ohta
Division of Child Health and Welfare, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Search for more papers by this authorCorresponding Author
Naoki Mori
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
Fax: +81-98-895-1410.
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, JapanSearch for more papers by this authorAbstract
Adult T-cell leukemia (ATL) is a fatal malignancy of T lymphocytes caused by human T-cell leukemia virus type 1 (HTLV-1) infection and remains incurable. Carotenoids are a family of natural pigments and have several biological functions. Among carotenoids, fucoxanthin is known to have antitumorigenic activity, but the precise mechanism of action is not elucidated. We evaluated the anti-ATL effects of fucoxanthin and its metabolite, fucoxanthinol. Both carotenoids inhibited cell viability of HTLV-1-infected T-cell lines and ATL cells, and fucoxanthinol was approximately twice more potent than fucoxanthin. In contrast, other carotenoids, β-carotene and astaxanthin, had mild inhibitory effects on HTLV-1-infected T-cell lines. Importantly, uninfected cell lines and normal peripheral blood mononuclear cells were resistant to fucoxanthin and fucoxanthinol. Both carotenoids induced cell cycle arrest during G1 phase by reducing the expression of cyclin D1, cyclin D2, CDK4 and CDK6, and inducing the expression of GADD45α, and induced apoptosis by reducing the expression of Bcl-2, XIAP, cIAP2 and survivin. The induced apoptosis was associated with activation of caspase-3, -8 and -9. Fucoxanthin and fucoxanthinol also suppressed IκBα phosphorylation and JunD expression, resulting in inactivation of nuclear factor-κB and activator protein-1. Mice with severe combined immunodeficiency harboring tumors induced by inoculation of HTLV-1-infected T cells responded to treatment with fucoxanthinol with suppression of tumor growth, showed extensive tissue distribution of fucoxanthinol, and the presence of therapeutically effective serum concentrations of fucoxanthinol. Our preclinical data suggest that fucoxanthin and fucoxanthinol could be potentially useful therapeutic agents for patients with ATL. © 2008 Wiley-Liss, Inc.
References
- 1 Poiesz BJ,Ruscetti FW,Gazdar AF,Bunn PA,Minna JD,Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA 1980; 77: 7415–9.
- 2 Hinuma Y,Nagata K,Hanaoka M,Nakai M,Matsumoto T,Kinoshita K,Shirakawa S,Miyoshi I. Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci USA 1981; 78: 6476–80.
- 3 Yoshida M,Miyoshi I,Hinuma Y. Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. Proc Natl Acad Sci USA 1982; 79: 2031–5.
- 4 Yamada Y,Tomonaga M,Fukuda H,Hanada S,Utsunomiya A,Tara M,Sano M,Ikeda S,Takatsuki K,Kozuru M,Araki K,Kawano F, et al. A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma: Japan Clinical Oncology Group Study 9303. Br J Haematol 2001; 113: 375–82.
- 5 van Poppel G,van den Berg H. Vitamins and cancer. Cancer Lett 1997; 114: 195–202.
- 6 Kim JM,Araki S,Kim DJ,Park CB,Takasuka N,Baba-Toriyama H,Ota T,Nir Z,Khachik F,Shimidzu N,Tanaka Y,Osawa T, et al. Chemopreventive effects of carotenoids and curcumins on mouse colon carcinogenesis after 1,2-dimethylhydrazine initiation. Carcinogenesis 1998; 19: 81–5.
- 7 Shiratori K,Ohgami K,Ilieva I,Jin X-H,Koyama Y,Miyashita K,Yoshida K,Kase S,Ohno S. Effects of fucoxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo. Exp Eye Res 2005; 81: 422–8.
- 8 Kotake-Nara E,Kushiro M,Zhang H,Sugawara T,Miyashita K,Nagao A. Carotenoids affect proliferation of human prostate cancer cells. J Nutr 2001; 131: 3303–6.
- 9 Hosokawa M,Kudo M,Maeda H,Kohno H,Tanaka T,Miyashita K. Fucoxanthin induces apoptosis and enhances the antiproliferative effect of the PPARγ ligand, troglitazone, on colon cancer cells. Biochim Biophys Acta 2004; 1675: 113–9.
- 10 Nomura T,Kikuchi M,Kubodera A,Kawakami Y. Proton-donative antioxidant activity of fucoxanthin with 1,1-diphenyl-2-picrylhydrazyl (DPPH). Biochem Mol Biol Int 1997; 42: 361–70.
- 11 Asai A,Sugawara T,Ono H,Nagao A. Biotransformation of fucoxanthinol into amarouciaxanthin A in mice and HepG2 cells: formation and cytotoxicity of fucoxanthin metabolites. Drug Metab Dispos 2004; 32: 205–11.
- 12 Miyoshi I,Kubonishi I,Yoshimoto S,Akagi T,Ohtsuki Y,Shiraishi Y,Nagata K,Hinuma Y. Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells. Nature 1981; 294: 770–1.
- 13 Yamamoto N,Okada M,Koyanagi Y,Kannagi M,Hinuma Y. Transformation of human leukocytes by cocultivation with an adult T cell leukemia virus producer cell line. Science 1982; 217: 737–9.
- 14 Maeda M,Shimizu A,Ikuta K,Okamoto H,Kashihara M,Uchiyama T,Honjo T,Yodoi J. Origin of human T-lymphotrophic virus I-positive T cell lines in adult T cell leukemia. Analysis of T cell receptor gene rearrangement. J Exp Med 1985; 162: 2169–74.
- 15 Mori N,Matsuda T,Tadano M,Kinjo T,Yamada Y,Tsukasaki K,Ikeda S,Yamasaki Y,Tanaka Y,Ohta T,Iwamasa T,Tomonaga M, et al. Apoptosis induced by the histone deacetylase inhibitor FR901228 in human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells. J Virol 2004; 78: 4582–90.
- 16 Zhang C,Ao Z,Seth A,Schlossman SF. A mitochondrial membrane protein defined by a novel monoclonal antibody is preferentially detected in apoptotic cells. J Immunol 1996; 157: 3980–7.
- 17 Mori N,Fujii M,Ikeda S,Yamada Y,Tomonaga M,Ballard DW,Yamamoto N. Constitutive activation of NF-κB in primary adult T-cell leukemia cells. Blood 1999; 93: 2360–8.
- 18 Dolcet X,Llobet D,Pallares J,Matias-Guiu X. NF-kB in development and progression of human cancer. Virchows Arch 2005; 446: 475–82.
- 19 Sun S-C,Yamaoka S. Activation of NF-κB by HTLV-I and implications for cell transformation. Oncogene 2005; 24: 5952–64.
- 20 Kawakami H,Tomita M,Matsuda T,Ohta T,Tanaka Y,Fujii M,Hatano M,Tokuhisa T,Mori N. Transcriptional activation of survivin through the NF-κB pathway by human T-cell leukemia virus type I Tax. Int J Cancer 2005; 115: 967–74.
- 21 Stehlik C,de Martin R,Kumabashiri I,Schmid JA,Binder BR,Lipp J. Nuclear factor (NF)-κB-regulated X-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor α-induced apoptosis. J Exp Med 1998; 188: 211–6.
- 22 Chu ZL,McKinsey TA,Liu L,Gentry JJ,Malim MH,Ballard DW. Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-κB control. Proc Natl Acad Sci USA 1997; 94: 10057–62.
- 23 Grossmann M,O'Reilly LA,Gugasyan R,Strasser A,Adams JM,Gerondakis S. The anti-apoptotic activities of Rel and RelA required during B-cell maturation involve the regulation of Bcl-2 expression. EMBO J 2000; 19: 6351–60.
- 24 Hinz M,Krappmann D,Eichten A,Heder A,Scheidereit C,Strauss M. NF-κB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol Cell Biol 1999; 19: 2690–8.
- 25 Huang Y,Ohtani K,Iwanaga R,Matsumura Y,Nakamura M. Direct trans-activation of the human cyclin D2 gene by the oncogene product Tax of human T-cell leukemia virus type I. Oncogene 2001; 20: 1094–102.
- 26 Iwanaga R,Ohtani K,Hayashi T,Nakamura M. Molecular mechanism of cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I. Oncogene 2001; 20: 2055–67.
- 27 Chen ZJ,Parent L,Maniatis T. Site-specific phosphorylation of IκBα by a novel ubiquitination-dependent protein kinase activity. Cell 1996; 84: 853–62.
- 28 Hall WW,Fujii M. Deregulation of cell-signaling pathways in HTLV-1 infection. Oncogene 2005; 24: 5965–75.
- 29 Utsunomiya A,Miyazaki Y,Takatsuka Y,Hanada S,Uozumi K,Yashiki S,Tara M,Kawano F,Saburi Y,Kikuchi H,Hara M,Sao H, et al. Improved outcome of adult T cell leukemia/lymphoma with allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 27: 15–20.
- 30 Griffin J. The biology of signal transduction inhibition: basic science to novel therapies. Semin Oncol 2001; 28: 3–8.
- 31 Satomi Y,Nishino H. Fucoxanthin, a natural carotenoid, induced G1 arrest and GADD45 gene expression in human cancer cells. In Vivo 2007; 21: 305–309.
- 32 Kroemer G,Reed JC. Mitochondrial control of cell death. Nat Med 2000; 6: 513–9.
- 33 Deveraux QL,Roy N,Stennicke HR,Van Arsdale T,Zhou Q,Srinivasula SM,Alnemri ES,Salvesen GS,Reed JC. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 1998; 17: 2215–23.
- 34 Shin S,Sung BJ,Cho YS,Kim HJ,Ha NC,Hwang JI,Chung CW,Jung YK,Oh BH. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry 2001; 40: 1117–23.
- 35 Hess J,Angel P,Schorpp-Kistner M. AP-1 subunits: quarrel and harmony among siblings. J Cell Sci 2004; 117: 5965–73.
- 36 Shaulian E,Karin M. AP-1 in cell proliferation and survival. Oncogene 2001; 20: 2390–400.
- 37 Brooks AR,Shiffman D,Chan CS,Brooks EE,Milner PG. Functional analysis of the human cyclin D2 and cyclin D3 promoters. J Biol Chem 1996; 271: 9090–9.
- 38 Grassmann R,Aboud M,Jeang K-T. Molecular mechanisms of cellular transformation by HTLV-1 Tax. Oncogene 2005; 24: 5976–85.
- 39 Mori N,Fujii M,Iwai K,Ikeda S,Yamasaki Y,Hata T,Yamada Y,Tanaka Y,Tomonaga M,Yamamoto N. Constitutive activation of transcription factor AP-1 in primary adult T-cell leukemia cells. Blood 2000; 95: 3915–21.
- 40 Matsuoka M. Human T-cell leukemia virus type I (HTLV-I) infection and the onset of adult T-cell leukemia (ATL). Retrovirology 2005; 2: 27.
Citing Literature
