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

Kaoru Otsu1, Kazuaki Sato, Yoshitaka Ikeda

  • 1Department of Biomolecular Function, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata 990-9585, Japan.

The Biochemical Journal
|March 31, 2005
PubMed

Insights

Singlet oxygen, generated by endoperoxides, causes tumor cell death in photodynamic therapy. This process involves mitochondrial damage and cytochrome c release, leading to a unique form of apoptosis with impaired caspase activation.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Photodynamic Therapy

Background:

  • Singlet oxygen is a key cytotoxic agent in photodynamic therapy (PDT).
  • The precise mechanisms of singlet oxygen-induced cell damage remain incompletely understood.
  • Investigating singlet oxygen's role in apoptosis is crucial for optimizing PDT strategies.

Purpose of the Study:

  • To elucidate the mechanism of singlet oxygen-induced cytotoxicity.
  • To compare the effects of two endoperoxides with defined singlet oxygen generation.
  • To investigate the role of mitochondrial damage and caspase activation in singlet oxygen-mediated cell death.

Main Methods:

  • Synthesis and application of two endoperoxides: 1-methylnaphthalene-4-propionate endoperoxide (MNPE) and naphthalene-1,4-dipropionate endoperoxide (NDPE).
  • Assessment of cytotoxicity, cytochrome c release, and DNA damage in response to endoperoxides.
  • Evaluation of cellular resistance in RBL cells overexpressing mitochondrial glutathione peroxidase.
  • Measurement of caspase 9 and 3 activities.

Main Results:

  • The more hydrophobic MNPE induced cytotoxicity and cytochrome c release, while NDPE did not.
  • RBL cells overexpressing mitochondrial glutathione peroxidase showed resistance to MNPE.
  • MNPE treatment resulted in less DNA laddering and nuclear fragmentation compared to etoposide.
  • Singlet oxygen directly inhibited caspase 9 and 3 activities, suppressing the caspase cascade.

Conclusions:

  • Singlet oxygen triggers apoptosis via mitochondrial component peroxidation and cytochrome c release.
  • Cell death induced by singlet oxygen differs from typical apoptosis due to impaired caspase activation.
  • Understanding this unique apoptotic pathway is vital for advancing photodynamic therapy.

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