Photodynamic activity of a glucoconjugated silicon(IV) phthalocyanine on human colon adenocarcinoma.
Photodynamic therapy (PDT) involves the use of a non-toxic photosensitizer which exhibits a killing effect upon activation by light. In the past few years, we have synthesized a number of novel second generation photosensitizers with superior properties, most of them are phthalocyanines. Among them, the glucoconjugated silicon(IV) phthalocyanine (SiPcGlu) shows potent phototoxicity against human colorectal adenocarcinoma HT29 cells. In the present study, its action mechanism was investigated. The initiation of apoptosis by SiPcGlu-PDT, subsequent to reactive oxygen species production, was shown by the results of TUNEL assay, annexin V and propidium iodide staining and DNA ladder pattern analysis. Confocal microscopy revealed the presence of SiPcGlu in lysosome, mitochondria and endoplasmic reticulum. SiPcGlu-PDT did not cause any damage to the lysosomal membrane; whereas in the mitochondria, it caused membrane depolarization and the release of cytochrome c into the cytosol, which subsequently brought about caspase-3 activation. In the endoplasmic reticulum, the treatment led to Ca(2+) release and an increase in the expression level of the chaperone protein GRP78. These observations suggest that SiPcGlu-PDT triggered the apoptotic pathways in both mitochondria and endoplasmic reticulum, but not the lysosome. A preliminary study of the photodynamic activity of SiPcGlu in the in vivo animal model was also carried out. It retarded tumor growth in HT29 tumor-bearing nude mice while causing no apparent toxicity to the animal.
Chan
Crystal M H
CM
Department of Biochemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
Lo
Pui-Chi
PC
Yeung
Sin-Lui
SL
Ng
Dennis K P
DK
Fong
Wing-Ping
WP
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053938:DNA Fragmentation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D019073:HT29 Cells; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D054833:Isoindoles; D008247:Lysosomes / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D007211:Indoles; D054833:Isoindoles; D017319:Photosensitizing Agents; D017382:Reactive Oxygen Species; C013647:phthalocyanine