benzyloxycarbonylleucyl-leucyl-leucine-aldehyde and deguelin

Diabetic nephropathy (DN), the leading cause of end-stage renal disease (ESRD). To date, mounting evidence has shown that inflammation may contribute to the pathogenesis of DN. Recent reports have shown that proteasome inhibitors display cytoprotection by reducing the phosphorylation of Akt, a serine/threonine kinase, plays a critical role in cellular survival and metabolism and can crosstalk with inflammation. Therefore, we hypothesized that MG132, specific proteasome inhibitor, could provide renoprotection by suppressing Akt-mediated inflammation in DN. In vivo, male Sprague-Dawley rats were divided into normal control group (NC), diabetic nephropathy group (DN), DN model plus MG132 treatment group (MG132), and DN model plus deguelin treatment group (Deguelin)(deguelin, a specific inhibitor of Akt). In vitro, a human glomerular mesangial cell lines (HMCs) was exposed to 5.5 mmol/L glucose (CON), 30 mmol/L glucose (HG), 30 mmol/L glucose with 0.5 umol/L MG132 (MG132) and 30 mmol/L glucose with 5 umol/L deguelin (Deguelin). Compared with NC, DN showed a significant increase in the urinary protein excretion rate and inflammatory cytokines, as well as p-Akt. Compared with CON, HMCs co-cultured with HG was notably proliferated, which is in accord with α-smooth muscle actin (α-SMA) expression. These alterations were inhibited by administration of MG132 or deguelin. In conclusion, MG132 significantly inhibits the development of DN by regulating Akt phosphorylation-mediated inflammatory activation.

Topics: Animals; Cell Line; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Glomerular Mesangium; Glucose; Humans; Inflammation; Inflammation Mediators; Kidney; Leupeptins; Male; Mesangial Cells; Proteasome Inhibitors; Protective Agents; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Rotenone; Signal Transduction

Hypoxia-inducible factor 1 (HIF-1) plays an essential role in tumor angiogenesis and growth by regulating the transcription of several genes in response to hypoxic stress and changes in growth factors. This study was designed to investigate the effects of deguelin on tumor growth and angiogenesis, and the mechanisms underlying the antitumor activities of deguelin. We show here that orally administered deguelin inhibits tumor growth and blocks tumor angiogenesis in mice. Deguelin decreased expression of HIF-1alpha protein and its target genes, such as VEGF, in a subset of cancer cell lines, including H1299 lung cancer cells, and vascular endothelial cells in normoxic and hypoxic conditions. Overexpression of vascular endothelial growth factor by adenoviral vector infection abolished the antiangiogenic effects of deguelin on H1299 nonsmall cell lung cancer cells. Deguelin inhibited de novo synthesis of HIF-1alpha protein and reduced the half-life of the synthesized protein. MG132, a proteasome inhibitor, protected the hypoxia- or IGF-induced HIF-1alpha protein from deguelin-mediated degradation. Our findings suggest that deguelin is a promising antiangiogenic therapeutic agent in cancer targeting HIF-1alpha. Considering that HIF-1alpha is overexpressed in a majority of human cancers, deguelin could offer a potent therapeutic agent for cancer.

Topics: Angiogenesis Inhibitors; Animals; Animals, Genetically Modified; Aorta; Blotting, Western; Cell Hypoxia; Cell Movement; Cell Proliferation; Chick Embryo; Chorioallantoic Membrane; Collagen; Culture Media, Conditioned; Cysteine Proteinase Inhibitors; Drug Combinations; Endothelium, Vascular; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Laminin; Leupeptins; Luciferases; Mice; Neoplasms; Neovascularization, Pathologic; Proteasome Endopeptidase Complex; Proteoglycans; Reverse Transcriptase Polymerase Chain Reaction; Rotenone; Tumor Cells, Cultured; Ubiquitin; Vascular Endothelial Growth Factor A; Zebrafish