title: Anticancer effects of marine carotenoids, fucoxanthin and its deacetylated product, fucoxanthinol, on osteosarcoma.
abstract: Survival of osteosarcoma patients hinges on prevention or treatment of recurrent and metastatic lesions. Therefore, novel chemotherapeutics for more effective treatment and prevention of this disease are required. Carotenoids are natural pigments and exhibit various biological functions. We evaluated the anti-osteosarcoma properties of several carotenoids. Among carotenoids, fucoxanthin and its metabolite fucoxanthinol, inhibited the cell viability of osteosarcoma cell lines. Fucoxanthinol induced G1 cell cycle arrest by reducing the expression of cyclin-dependent kinase 4, cyclin-dependent kinase 6 and cyclin E and apoptosis by reducing the expression of survivin, XIAP, Bcl-2 and Bcl-xL. Apoptosis was associated with activation of caspases-3, -8 and -9. In addition, fucoxanthinol inhibited the phosphorylation of phosphoinositide-dependent kinase 1 and Akt and the downstream glycogen synthase kinase 3β, resulting in downregulation of β-catenin. Fucoxanthinol inhibited the cell migration and invasion of osteosarcoma cells. It also reduced matrix metalloproteinase-1 expression and the activator protein-1 signal. Treatment of mice inoculated with osteosarcoma cells with fucoxanthin inhibited the development of osteosarcoma in mice. Fucoxanthin and fucoxanthinol inhibit cell growth, migration and invasion and induce apoptosis of osteosarcoma cells at least in part by inhibiting Akt and activator protein-1 pathways. Our findings provide a rationale for clinical evaluation of these novel agents in osteosarcoma.
authors.affiliation: Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Rokkaku
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Kimura
authors.forename: Chie
authors.initials: C
authors.lastname: Ishikawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yasumoto
authors.forename: Masachika
authors.initials: M
authors.lastname: Senba
authors.forename: Fuminori
authors.initials: F
authors.lastname: Kanaya
authors.forename: Naoki
authors.initials: N
authors.lastname: Mori
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002338:Carotenoids / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D006801:Humans; D051379:Mice; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D024341:Xanthophylls / Q000008:administration & dosage*; D019207:beta Carotene / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000970:Antineoplastic Agents; D024341:Xanthophylls; D019207:beta Carotene; C025164:fucoxanthin; D002338:Carotenoids; C483031:fucoxanthinol; D051057:Proto-Oncogene Proteins c-akt; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6