RESUMO
Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs and are now in clinical trial. We have previously shown that farnesylamine, synthetic isoprenoid-linked with "amine" which acts as a potent FTI, induces apoptosis in human pancreatic cancer cells through the ras signaling cascade. Since the effect of FTI is usually "cytostatic" rather than "cytotoxic", we speculated another apoptotic machinery of farnesylamine in addition to the effect of FTI. Farnesylamine induced sustained activation of c-jun N-terminal kinase (JNK), which was not caused by other FTI, FTI-277. Blockage of JNK activity by dominant-negative mutant abrogated the DNA laddering and significantly reduced "cytotoxic" effect of farnesylamine. Strikingly similar effect on JNK activation and apoptosis was induced by structurally related long-chain fatty amine (LFA), oleylamine, but not by farnesol, an isoprenoid analogue of farnesylamine without "amine." Taken together, apoptosis induction through JNK activation by farnesylamine based on the LFA structure rather than an effect of FTI.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose , Farneseno Álcool/análogos & derivados , Farneseno Álcool/farmacologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Neoplasias Pancreáticas/enzimologia , Aminas/farmacologia , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase , Genes ras , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno , Sistema de Sinalização das MAP Quinases , Proteína Quinase 8 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/genética , Mutação , Neoplasias Pancreáticas/patologia , Células Tumorais CultivadasRESUMO
The reaction conditions of 1,3-diethyl-2-thiobarbituric acid (DETBA)-malonaldehyde (MA) adduct formation were examined in order to analyze MA in fish tissue by high-performance liquid chromatography. A reaction mixture containing 4 mM butyl hydroxytoluene was heated at 100 degrees C for 150 min and the DETBA-MA adduct formed was separated by a Inertsil ODS column for 20 min. The detection limit was 5 pmol.