RESUMO
Bucillamine is used for the treatment of rheumatoid arthritis. This study investigated the protective effects of bucillamine against cisplatin-induced damage in auditory cells, the organ of Corti from postnatal rats (P2) and adult Balb/C mice. Cisplatin increases the catalytic activity of caspase-3 and caspase-8 proteases and the production of free radicals, which were significantly suppressed by pretreatment with bucillamine. Bucillamine induces the intranuclear translocation of Nrf2 and thereby increases the expression of gamma-glutamylcysteine synthetase (gamma-GCS) and glutathione synthetase (GSS), which further induces intracellular antioxidant glutathione (GSH), heme oxygenase 1 (HO-1) and superoxide dismutase 2 (SOD2). However, knockdown studies of HO-1 and SOD2 suggest that the protective effect of bucillamine against cisplatin is independent of the enzymatic activity of HO-1 and SOD. Furthermore, pretreatment with bucillamine protects sensory hair cells on organ of Corti explants from cisplatin-induced cytotoxicity concomitantly with inhibition of caspase-3 activation. The auditory-brainstem-evoked response of cisplatin-injected mice shows marked increases in hearing threshold shifts, which was markedly suppressed by pretreatment with bucillamine in vivo. Taken together, bucillamine protects sensory hair cells from cisplatin through a scavenging effect on itself, as well as the induction of intracellular GSH.
Assuntos
Animais , Masculino , Camundongos , Ratos , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Linhagem Celular , Cisplatino/toxicidade , Cisteína/análogos & derivados , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Glutationa/metabolismo , Heme Oxigenase-1/genética , Espaço Intracelular/metabolismo , Desintoxicação Metabólica Fase II/genética , Fator 2 Relacionado a NF-E2/genética , Óxido Nítrico/biossíntese , Órgão Espiral/efeitos dos fármacos , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/genéticaRESUMO
Genetic influences on cancer development have been extensively investigated during the last decade following publication of human genome sequence. The present review summarizes case-control studies on genetic polymorphisms and cancer risk in Indians. It is observed that the most commonly studied genes in the Indian population included members of phase I and phase II metabolic enzymes. Other than these genes, genetic polymorphisms for cell cycle and apoptosis-related factors, DNA repair enzymes, immune response elements, growth factors, folate metabolizing enzymes, vitamin/hormone receptors, etc., were investigated. Several studies also evidenced a stronger risk for combined genotypes rather than a single polymorphism. Gene-environment interaction was also found to be a determining factor for cancer development in some experiments. Data for single polymorphism and single cancer type, however, was insufficient to validate an association. It appears that much more experiments involving larger sample size, cross-tabulating genetic polymorphisms and environmental factors are required in order to identify genetic markers for different cancers in Indian populations.