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

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, cyclindependent 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. Introduction Osteosarcoma is the most frequent malignant bone tumor in children and adolescents and the estimated worldwide incidence ranges between 3 and 4.5 per million (1). Long-term survival in localized osteosarcoma has increased substantially from 10-20% when surgery as single treatment was used before the 1980's up to 20-60% from 1985 onwards. The improvement in survival has been attributed to the use of intensive multiagent chemotherapy in combination with advanced surgery. However, since then no substantial further improvement of survival has been reported (2). Despite aggressive multimodal therapy, this devastating tumor often acquires drug resistance and metastasizes (3). The most frequent site for metastatic presentation is the lung (3). Death from osteosarcoma is usually the result of progressive pulmonary metastasis with respiratory failure due to widespread disease (3). Hence, there is a real need to develop novel approaches for the treatment and prevention of osteosarcoma and efficient inhibition of metastasis, especially to the lung. The role of carotenoids in reducing the risk of cancer has been postulated for several decades (4). Fucoxanthin, one of the most abundant carotenoids found in edible brown algae, has received much attention over the last few years as cancer chemopreventive and chemotherapeutic agent (5). Dietary fucoxanthin is deacetylated into fucoxanthinol in the intestinal tract by lipase and esterase from the pancreas or in intestinal cells and incorporated as fucoxanthinol from the digestive tract into the blood circulation system in mammals (5). These carotenoids exhibit antitumor effects in several malignant cell lines without affecting normal cells (5,6). The main mechanism is suggested to be the regulatory effects of fucoxanthin and fucoxanthinol on molecules related to apoptosis and cell cycle (5,6). Furthermore, it has been shown that fucoxanthin has chemopreventive activities in a variety of models of cancer (5). However, to date, there is no information on fucoxanthinand fucoxanthinol-induced inhibition of cell growth, migration and invasion of human bone cancer cells. In this study, we investigated the effects of fucoxanthin and Anticancer effects of marine carotenoids, fucoxanthin and its deacetylated product, fucoxanthinol, on osteosarcoma TAKAYOSHI ROKKAKU1,2, RYUICHIRO KIMURA1,3, CHIE ISHIKAWA1,3, TAKESHI YASUMOTO4, MASACHIKA SENBA5, FUMINORI KANAYA2 and NAOKI MORI1 Departments of 1Microbiology and Oncology and 2Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215; 3Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, Nishihara, Okinawa 903-0213; 4Marine Bio Industry Division, Okinawa Science and Technology Promotion Center, Naha, Okinawa 900-0029; 5Department of Pathology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan Received April 25, 2013; Accepted June 7, 2013 DOI: 10.3892/ijo.2013.2019 Correspondence to: Professor Naoki Mori, Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan E-mail: [email protected]