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

Abstract

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 degrees 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.

Difference in the Cytotoxic Effects of Toxin B fromClostridium difficileStrain VPI 10463 and Toxin B from VariantClostridium difficileStrain 1470

“…RBL cells are sensitive to glucosylating toxins and are a well-established cell line for studying apoptotic cell death; furthermore, RBL cells can be synchronized using the thymidine double-block technique (20,35,36,42). RBL cells were cultured in minimum essential medium supplemented with 15% heat-inactivated fetal calf serum, 100 g/ml penicillin, 100 U/ml streptomycin, and 1 mM sodium pyruvate.…”

Structural Analysis of Amino Acids, Oxidized by Reactive Oxygen Species and an Antibody against N-Formylkynurenine

“…We have recently shown that the cell death induced by singlet oxygen is atypical to apoptosis [18]. This is due to the suppression of the caspase cascade prior to apoptosome formation and the direct inhibition of caspase activity and the proapoptotic function of cytochrome c by singlet oxygen [18,19]. Despite extensive study, however, we were unable to identify the amino acid modification responsible for this, probably because of the complex nature of the oxidation products.…”

“…At the initial stage of apoptosis after the stimuli, cytochrome c is generally released from mitochondria and activates apoptosome formation, leading to the activation of the caspase cascade. We have recently shown that the cell death induced by singlet oxygen is atypical to apoptosis [18]. This is due to the suppression of the caspase cascade prior to apoptosome formation and the direct inhibition of caspase activity and the proapoptotic function of cytochrome c by singlet oxygen [18,19].…”

Trends in Interdisciplinary Studies Revealing Porphyrinic Compounds Multivalency Towards Biomedical Application

“…involves excitation of the photosensitizer with light, but energy is transferred in this case to the triplet ground state of molecular oxygen, resulting in excited singlet state oxygen which is highly cytotoxic (Otsu K et al, 2005). In type I mechanism, oxygen is not always necessary for the photodynamic action to take place; however, in type II mechanism, oxygen is essential.…”