gsk525762a and Cell-Transformation--Neoplastic

Almost half a million of all new cancers have been attributed to obesity and epidemiologic evidence implicates visceral adipose tissue (VAT) and high-fat diets (HFD) in increasing cancer risk. We demonstrated that VAT-derived fibroblast growth factor 2 (FGF2) from mice fed an HFD or obese individuals stimulates the malignant transformation of epithelial cells. Mechanism-based strategies to prevent this VAT-enhanced tumorigenesis have not been explored. Clinical studies have indicated that bromodomain inhibitors have considerable potential as therapeutic agents for cancer by inhibiting the activity of several oncogenes, including c-Myc; however, their chemopreventive activity is unknown. We show herein that mice with visceral adiposity have elevated nuclear c-Myc expression in their epidermis. We hypothesized that the bromodomain inhibitor I-BET-762 (I-BET) would have efficacy in the prevention of malignant transformation by VAT and FGF2. We tested this hypothesis using our novel models of VAT-stimulated transformation

Topics: Adiposity; Animals; Antineoplastic Agents; Benzodiazepines; Cell Transformation, Neoplastic; Cells, Cultured; Female; Gene Expression Regulation, Neoplastic; Humans; Intra-Abdominal Fat; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Obesity; Proteins; Proto-Oncogene Proteins c-myc; Xenograft Model Antitumor Assays