Osteosarcoma remains the most common primary malignant bone cancer affecting children and adolescents. Although the combination of systemic chemotherapy and surgery enables long‐term survival in most cases, the poor prognosis of patients with metastatic or recurrent disease and the lack of establishment of second‐line chemotherapy suggest that novel therapeutic strategies for this tumor are needed. Here we show that fenretinide, a synthetic derivative of all‐trans‐retinoic acid, is active against osteosarcoma in vitro, at concentrations identical or lower to those detectable in breast cancer patients plasma during chemopreventive clinical trials. Cell lines were HOS and MG63, known to be resistant to methotrexate and cyclophosphamide, drugs in use in osteosarcoma treatment. We demonstrate for the first time that fenretinide is active in this tumor and that the molecular basis of fenretinide activity is the inhibition of cholesterol esterification, with down‐regulation of ACAT and MDR1 mRNA, followed by downregulation of caveolin‐1 protein expression. This result is in line with our recent results obtained in VSMC and in leukemia cells. The confirmation and extention of these data to different human tumors will provide evidence of a novel mechanism of either cancer or human vascular proliferation disease control by the inhibition of cholesterol esterification. Grants from MIUR, Carisbo Foundation, Pallotti's Legacy for Cancer Research and University of Bologna.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C84.
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