Article

DNA damage and apoptosis induced by photosensitization of 5,10,15,20-tetrakis (N-methyl-4-pyridyl)-21H,23H-porphyrin via singlet oxygen generation.

Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
Photochemistry and Photobiology (impact factor: 2.41). 08/2009; 85(6):1391-9. DOI:10.1111/j.1751-1097.2009.00600.x
Source: PubMed

ABSTRACT Cancer photodynamic therapy (PDT) requires photosensitizers that efficiently and selectively destroy tumor cells. We investigated 5,10,15,20-tetrakis (N-methyl-4-pyridyl)-21H,23H-porphyrin (TMPyP) as a potential cancer treatment. Confocal fluorescence microscopy showed that TMPyP was localized in the nuclei, whereas 5-aminolevulinic acid (ALA)-derived protoporphyrin IX (PPIX) was localized diffusely in the cytoplasm of human leukemia (HL-60) cells. In HL-60 cells under UVA irradiation, TMPyP effectively induced apoptosis. Moreover, 8-oxo-7,8-dihydro-2'-deoxyguanosine, an oxidative product of 2'-deoxyguanosine, was accumulated in the DNA of cells treated with photoirradiated TMPyP, whereas only small amounts were observed in ALA-treated cells in the presence of UVA light. TMPyP and UVA caused extensive damage at every guanine residue in DNA fragments obtained from the human p53 tumor suppressor gene and the c-Ha-ras-1 proto-oncogene, whereas PPIX induced little DNA damage under these conditions. Electron spin resonance spectroscopy using a singlet oxygen (1O2) probe and D2O showed that photoexcited TMPyP generated 1O2. These results suggest that photoexcited TMPyP reacts with oxygen to generate 1O2, which in turn, oxidizes guanine residues. Taken together, the results demonstrated that TMPyP was localized in the nucleus where it was photosensitized to induce DNA damage, suggesting that TMPyP may have clinical utility as a nucleus-targeted PDT.

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Keywords

5-aminolevulinic acid
 
ALA)-derived protoporphyrin IX
 
Cancer photodynamic therapy
 
Confocal fluorescence microscopy
 
DNA damage
 
extensive damage
 
guanine residue
 
HL-60 cells
 
induce DNA damage
 
nucleus-targeted PDT
 
oxidative product
 
oxidizes guanine residues
 
photoexcited TMPyP
 
photoirradiated TMPyP
 
potential cancer treatment
 
PPIX induced
 
resonance spectroscopy
 
small amounts
 
UVA irradiation
 
UVA light
 

Saeko Tada-Oikawa