RESUMO
Intracellular reactive oxygen species (ROS) such as hydrogen peroxide (H(2)O2()) are thought to mediate apoptosis induced by death receptor ligands, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). However, the role of H(2)O(2) is controversial, since some evidence suggests that H(2)O(2) acts as an anti-apoptotic factor. Here, we show that exogenously applied H(2)O(2) (30-100 µM) induces cell death in TRAIL-resistant human melanoma cells via intracellular superoxide (O(2)-) generation. H(2)O(2) induced apoptotic or necrotic cell death, depending on the concentration of the oxidant applied; low concentrations of H(2)O(2) preferentially activated the caspase-dependent apoptotic pathway, while high concentrations of H(2)O(2) induced apoptotic and necrotic cell death in a caspase-independent manner. The H(2)O(2)-induced cell death was associated with increased mitochondrial membrane potential collapse and caspase-3/7 activation and ER stress responses including caspase-12 and X-box-binding protein-1 (XBP-1) activation. H(2)O(2) induced intracellular O2- generation even within the mitochondria, while TRAIL did not. The superoxide dismutase mimetic antioxidant MnTBaP [Mn (III) tetrakis (4-benzonic acid) porphyrin chloride] inhibited the H(2)O(2)-induced O(2)- generation, apoptosis and XBP-1 and caspase-12 activation at comparable concentrations. Importantly, H(2)O(2) treatment caused minimal O(2)- generation and apoptosis in normal primary melanocytes. These data show that H(2)O(2) induces endoplasmic reticulum-associated cell death via intracellular O(2)- generation and that malignant melanoma cells are more susceptible than normal cells to this oxidative cell death. The findings suggest that H(2)O(2) has therapeutic potential in the treatment of TRAIL-resistant melanoma.
Assuntos
Apoptose/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Melanoma/metabolismo , Superóxidos/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Caspase 12/efeitos dos fármacos , Caspase 12/metabolismo , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Estresse do Retículo Endoplasmático , Ativação Enzimática , Sequestradores de Radicais Livres/farmacologia , Humanos , Potencial da Membrana Mitocondrial , Metaloporfirinas/farmacologia , Necrose , Fatores de Transcrição de Fator Regulador X , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Proteína 1 de Ligação a X-BoxRESUMO
We report a 63-year-old Japanese man with epilepsy who developed skin eruptions, liver dysfunction, high fever, leukocytosis and atypical lymphocytosis 4 weeks after he had started taking carbamazepine. Titers of human herpesvirus 7 (HHV-7)-specific IgG antibodies were significantly increased and HHV-7 DNA was detected in his serum by polymerase chain reaction. These findings suggested that reactivation of HHV-7 could contribute to the development of drug-induced hypersensitivity syndrome.
