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Rapid induction of apoptosis in human keratinocytes with the photosensitizer QLT0074 via a direct mitochondrial action.
- Source :
-
Apoptosis : an international journal on programmed cell death [Apoptosis] 2003 Jun; Vol. 8 (3), pp. 269-75. - Publication Year :
- 2003
-
Abstract
- QLT0074 is a newly introduced, porphyrin-derivative for use in photodynamic therapy (PDT). In the current study, the intracellular distribution of QLT0074 and the mode of cell death induced by photosensitization with this compound in vitro were assessed for transformed human HaCaT keratinocytes. Fluorescence microscopy studies indicated a distribution of the drug to the cytoplasm, nuclear membrane and mitochondria of these cells. In the absence of light, QLT0074 produced no evidence of apoptosis-related biochemical changes or affected cell viability. When combined with blue light exposure, cytotoxicity was exerted in a QLT0074- and light-dose-related manner. Appearance of the mitochondrial protein cytochrome c in the cytosolic fraction and expression of the apoptosis-associated mitochondrial 7A6 antigen were demonstrable following photosensitization at nano-molar levels of QLT0074. Evidence of processing of the apoptosis-effector molecules caspase-3, -6, -7, -8 and -9 as well as cleavage of the caspase-3 substrate poly (ADP-ribose) polymerase (PARP) were demonstrable subsequent to cytochrome c release after PDT. Treatment with the anti-oxidant pyrrolidine dithiocarbamate (PDTC) inhibited cytochrome c release, caspase-3 activation and PARP cleavage associated with PDT thereby supporting the contention that QLT0074 induces apoptosis through the generation of reactive oxygen species upon light activation. QLT0074 is a potent photosensitizer with the capacity to directly initiate apoptosis by acting upon mitochondria.
- Subjects :
- Antioxidants pharmacology
Apoptosis radiation effects
Caspases drug effects
Caspases radiation effects
Cell Compartmentation drug effects
Cell Compartmentation physiology
Cell Line, Transformed
Cytochromes c drug effects
Cytochromes c radiation effects
Dose-Response Relationship, Drug
Humans
Keratinocytes metabolism
Keratinocytes radiation effects
Membrane Proteins drug effects
Membrane Proteins radiation effects
Mitochondria metabolism
Mitochondria radiation effects
Photic Stimulation
Photochemotherapy
Photosensitizing Agents radiation effects
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases
Porphyrins radiation effects
Proteins drug effects
Proteins radiation effects
Pyrrolidines pharmacology
Reaction Time drug effects
Reaction Time radiation effects
Reactive Oxygen Species metabolism
Thiocarbamates pharmacology
Apoptosis drug effects
Keratinocytes drug effects
Mitochondria drug effects
Photosensitizing Agents toxicity
Porphyrins pharmacology
Porphyrins toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1360-8185
- Volume :
- 8
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Apoptosis : an international journal on programmed cell death
- Publication Type :
- Academic Journal
- Accession number :
- 12766487
- Full Text :
- https://doi.org/10.1023/a:1023624922787