RESUMO
MafBx and Murf are two new rat E3 ubiquitin ligases induced in muscle atrophy. Our goal was to investigate whether lipopolysaccharide (LPS) injection, a model of muscle catabolism, is associated with increased expression of MafBx and Murf. LPS (750 microg/100 g body weight) induces MafBx and Murf mRNA (respectively, 23-fold and 33-fold after 12 h; P<0.001). A transient induction of tumor necrosis factor-alpha mRNA (21-fold; P<0.001 at 3 h) and a decrease of insulin like growth factor-I mRNA (50%; P<0.001 at 6 h), two potential regulators of the ubiquitin-proteasome system were also demonstrated. In summary, MafBx and Murf mRNA are up-regulated in response to LPS and might play a role in the muscle proteolysis observed.
Assuntos
Ligases/metabolismo , Lipopolissacarídeos/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Proteínas Ligases SKP Culina F-Box , Ubiquitina-Proteína Ligases , Animais , Peso Corporal , Músculo Esquelético/efeitos dos fármacos , Músculos/metabolismo , RNA/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Proteínas com Motivo Tripartido , Fator de Necrose Tumoral alfa/metabolismo , Regulação para CimaRESUMO
Several naphthalimides have been evaluated clinically as potential anticancer agents. UNBS3157, a naphthalimide that belongs to the same class as amonafide, was designed to avoid the specific activating metabolism that induces amonafide's hematotoxicity. The current study shows that UNBS3157 rapidly and irreversibly hydrolyzes to UNBS5162 without generating amonafide. In vivo UNBS5162 after repeat administration significantly increased survival in orthotopic human prostate cancer models. Results obtained by the National Cancer Institute (NCI) using UNBS3157 and UNBS5162 against the NCI 60 cell line panel did not show a correlation with any other compound present in the NCI database, including amonafide, thereby suggesting a unique mechanism of action for these two novel naphthalimides. Affymetrix genome-wide microarray analysis and enzyme-linked immunosorbent assay revealed that in vitro exposure of PC-3 cells to UNBS5162 (1 microM for 5 successive days) dramatically decreased the expression of the proangiogenic CXCL chemokines. Histopathology additionally revealed antiangiogenic properties in vivo for UNBS5162 in the orthotopic PC-3 model. In conclusion, the present study reveals UNBS5162 to be a pan-antagonist of CXCL chemokine expression, with the compound displaying antitumor effects in experimental models of human refractory prostate cancer when administered alone and found to enhance the activity of taxol when coadministered with the taxoid.