cerulenin and Disease-Models--Animal

Polymorphonuclear cells (PMN) activation is an essential step in acute pancreatitis (AP). We investigated the activation status of PMN, oxidative stress and pancreatic damage in early stage of experimental ceruleine pancreatitis in rats. The PMN action was modulated by monoclonal antibody CD 11b administration. The circulating WBC and polymorphonuclear cells count was reduced after AP induction. Chemiluminescence of whole blood PMN was remarkably reduced in AP group and increased after MoAb CD 11b administration. The CD 11b blockade significantly reduced the WBC infiltration and malondialdehyde (MDA) concentration within pancreatic gland. These data suggest that activated PMN are an important factor in early AP pathogenesis. Neutrophil aggregation within pancreatic gland modulated by monoclonal antibody CD11b contribute to the extent of injury during the early stage of ceruleine experimental pancreatitis in rats.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Monoclonal; Antifungal Agents; CD11b Antigen; Cerulenin; Disease Models, Animal; Leukocyte Elastase; Luminescent Measurements; Lymphocyte Activation; Male; Malondialdehyde; Neutrophils; Pancreas; Pancreatitis; Peroxidase; Rats; Rats, Wistar

Fatty acid synthase (FAS) is the major enzyme required to convert carbohydrates to fatty acids. Recent evidence suggests that FAS activity is essential for prostate cancer growth and survival, since blocking the enzyme activity results in cell death. In this study, the role of FAS up-regulation during prostate tumor progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model was investigated. Sensitivity to FAS anti-metabolites was also analyzed in TRAMP prostate tumor cells and tissue to determine therapeutic potential of FAS inhibition in the treatment of prostate cancer.. FAS expression was evaluated by immunohistochemistry of TRAMP tissues, including primary and metastatic lesions in mice of varying ages. FAS pathway activity was studied in vitro using TRAMP-derived cell lines and in vivo in TRAMP tissues. The sensitivity of TRAMP cell lines and tissues to the antimetabolite drugs (2R,3S)-2,3-epoxy-4-oxo-7,10-trans, transdodecadienamide (cerulenin) and C-75, which target FAS, was determined by FAS antimetabolite inhibition of 14C-acetate conversion to fatty acids, cell growth inhibition, and apoptosis analyses.. High FAS expression and activity in the TRAMP mouse prostate was evident at 12 weeks of age compared with nontransgenic littermates and further increased with age, tumor progression, and in metastatic lesions. FAS pathway inhibition resulted in a dose-dependent reduction in cell survival and decreased enzyme activity in these models.. These data suggest that the up-regulation of FAS expression play a role in tumorigenesis of the prostate in the TRAMP model and hence can provide valuable insight into human prostate cancer. Given the response of tumor cells to FAS antimetabolites, FAS may serve as a novel target for prostate cancer therapy.

Topics: Adenocarcinoma; Animals; Apoptosis; Blotting, Western; Cerulenin; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Fatty Acid Synthases; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Prostatic Neoplasms

Many common human cancer tissues express high levels of fatty acid synthase (FAS), the primary enzyme for the synthesis of fatty acids, and the differential expression of FAS between normal and neoplastic tissues has led to the consideration of FAS as a target for anticancer therapy. To investigate the potential of targeting FAS for the treatment of pleural mesothelioma, we first determined whether FAS is overexpressed in human mesothelioma. By immunohistochemistry, we found 22 of 30 human mesothelioma tissue samples tested to express significantly increased levels of FAS compared with normal tissues, including mesothelium. To further explore FAS as a therapeutic target in mesothelioma, we established a nude mouse xenograft model for human mesothelioma using the H-Meso cell line. The i.p. xenografts of this cell line have high levels of FAS expression and fatty acid synthesis pathway activity and grow along mesothelial surfaces in a manner similar to the growth pattern of human mesothelioma. Growth of these tumor xenografts was essentially abolished in mice treated with weekly i.p. injections of C75, a synthetic, small molecule inhibitor of FAS, at levels that resulted in no significant systemic toxicity except for reversible weight loss. These results suggest that FAS may be an effective target for pharmacological therapy in a high proportion of human mesotheliomas.

Topics: 4-Butyrolactone; Animals; Antifungal Agents; Antineoplastic Agents; Cerulenin; Disease Models, Animal; Fatty Acid Synthases; Humans; Immunoenzyme Techniques; Mesothelioma; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Mesothelial; Paraffin Embedding; Prognosis; Tumor Cells, Cultured