Subcellular Targeting as a Determinant of the Efficacy of Photodynamic Therapy
1Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI.
Abstract:
In prior studies, we have identified the ability of low-level lysosomal photodamage to potentiate the phototoxic effect of subsequent photodamage to mitochondria. The mechanism involves calpain-mediated cleavage of the autophagy-associated protein ATG5 to form a proapoptotic fragment (tATG5). In this report, we explore the permissible time lag between the two targeting procedures along with the effect of simultaneously targeting both lysosomes and mitochondria. This was found to be as effective as the sequential protocol with no gap between the irradiation steps. Inhibition of calpain reversed the enhanced efficacy of the "simultaneous" protocol. It appears that even a minor level of lysosomal photodamage can have a significant effect on the efficacy of subsequent mitochondrial photodamage. We propose that these results may explain the efficacy of Photofrin, a photosensitizing product that also targets both lysosomes and mitochondria for photodamage.
Insights
Low-level lysosomal photodamage enhances mitochondrial phototoxicity by activating calpain and cleaving ATG5. Simultaneous targeting of lysosomes and mitochondria is as effective as sequential targeting, suggesting a mechanism for Photofrin efficacy.
Area of Science:
- Cell Biology
- Photodynamic Therapy
Background:
- Lysosomal photodamage can potentiate mitochondrial phototoxicity.
- This potentiation involves calpain-mediated cleavage of ATG5 into a proapoptotic fragment (tATG5).
Purpose of the Study:
- To investigate the time lag permissible between lysosomal and mitochondrial photodamage.
- To evaluate the efficacy of simultaneously targeting both organelles.
Main Methods:
- Sequential and simultaneous photodynamic targeting of lysosomes and mitochondria.
- Calpain inhibition to assess its role in the observed effects.
Main Results:
- Simultaneous targeting was as effective as sequential targeting, even with no time gap.
- Calpain inhibition reversed the enhanced efficacy of the simultaneous protocol.
- Minor lysosomal photodamage significantly impacts subsequent mitochondrial photodamage efficacy.
Conclusions:
- The timing of lysosomal and mitochondrial photodamage is flexible, with simultaneous targeting being effective.
- Calpain activation is crucial for the synergistic phototoxic effect.
- These findings may explain the therapeutic efficacy of photosensitizers like Photofrin that target both lysosomes and mitochondria.
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