An abortive apoptotic pathway induced by singlet oxygen is due to the suppression of caspase activation.
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.
Otsu
Kaoru
K
Department of Biomolecular Function, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata 990-9585, Japan.
Sato
Kazuaki
K
Ikeda
Yoshitaka
Y
Imai
Hirotaka
H
Nakagawa
Yasuhito
Y
Ohba
Yoshihiro
Y
Fujii
Junichi
J
D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002474:Cell-Free System; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008054:Lipid Peroxides / Q000494:pharmacology; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D009284:Naphthols / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D012643:Selenium / Q000378:metabolism; D026082:Singlet Oxygen / Q000737:chemistry / Q000378:metabolism*; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives / Q000378:metabolism; D019207:beta Carotene / Q000378:metabolism
C114034:3-(4'-methyl-1'-naphthyl)propionic acid 1',4'-endoperoxide; D061945:Caspase Inhibitors; D008054:Lipid Peroxides; D009284:Naphthols; D011422:Propionates; D019207:beta Carotene; D014810:Vitamin E; D026082:Singlet Oxygen; D045304:Cytochromes c; C058008:3,3'-(1,4-naphthylidene)diproprionate; D020169:Caspases; D005978:Glutathione; D012643:Selenium; D024505:Tocopherols