An abortive apoptotic pathway induced by singlet oxygen is due to the suppression of caspase activation

AUTOR(ES)

Otsu, Kaoru

FONTE

Portland Press Ltd.

RESUMO

Singlet oxygen causes the cytotoxic process of tumour cells in photodynamic therapy. The mechanism by which singlet oxygen damages cells is, however, not fully understood. To address this issue, we synthesized and used two types of endoperoxides, MNPE (1-methylnaphthalene-4-propionate endoperoxide) and NDPE (naphthalene-1,4-dipropionate endoperoxide), that generate defined amounts of singlet oxygen at 37 °C with similar half lives. MNPE, which is more hydrophobic than NDPE, induced the release of cytochrome c from mitochondria into the cytosol and exhibited cytotoxicity, but NDPE did not. RBL cells, a rat basophil leukaemia-derived line, that overexpress phospholipid hydroperoxide glutathione peroxidase in mitochondria were found to be highly resistant to the cytotoxic effect of MNPE. MNPE treatment induced much less DNA ladder formation and nuclear fragmentation in cells than etoposide treatment, even though these treatments induced a similar extent of cellular damage. Singlet oxygen inhibited caspase 9 and 3 activities directly and also suppressed the activation of the caspase cascade. Collectively, these data suggest that singlet oxygen triggers an apoptotic pathway by releasing cytochrome c from mitochondria via the peroxidation of mitochondrial components and results in cell death that is different from typical apoptosis, because of the abortive apoptotic pathway caused by impaired caspase activation.

Documentos Relacionados

• Redirecting tyrosine kinase signaling to an apoptotic caspase pathway through chimeric adaptor proteins
• HIV-1 kills renal tubular epithelial cells in vitro by triggering an apoptotic pathway involving caspase activation and Fas upregulation.
• The JNK MAP kinase pathway contributes to the development of endotoxin-induced diaphragm caspase activation
• DNA synthesis blocking lesions induced by singlet oxygen are targeted to deoxyguanosines.
• Enzymatic recognition of DNA modifications induced by singlet oxygen and photosensitizers.