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Photodynamic activity of a glucoconjugated silicon(IV) phthalocyanine on human colon adenocarcinoma
Crystal M H Chan1, Pui-Chi Lo, Sin-Lui Yeung
1Department of Biochemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
Abstract:
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.
Insights
Glucoconjugated silicon(IV) phthalocyanine (SiPcGlu) in photodynamic therapy (PDT) effectively triggers apoptosis in colorectal cancer cells by targeting mitochondria and endoplasmic reticulum. SiPcGlu-PDT also demonstrated in vivo tumor growth retardation with minimal toxicity.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Photodynamic therapy (PDT) utilizes photosensitizers activated by light to induce cell death.
- Second-generation phthalocyanine photosensitizers, including glucoconjugated silicon(IV) phthalocyanine (SiPcGlu), offer enhanced properties.
- SiPcGlu exhibits significant phototoxicity against human colorectal adenocarcinoma HT29 cells.
Purpose of the Study:
- To investigate the detailed action mechanism of SiPcGlu-mediated photodynamic therapy (PDT).
- To elucidate the cellular pathways and organelles involved in SiPcGlu-PDT-induced apoptosis.
- To assess the in vivo efficacy and toxicity of SiPcGlu-PDT in a preclinical model.
Main Methods:
- Apoptosis induction was assessed using TUNEL assay, annexin V/propidium iodide staining, and DNA ladder analysis.
- Subcellular localization of SiPcGlu was determined by confocal microscopy.
- Mitochondrial membrane potential, cytochrome c release, caspase-3 activation, ER Ca(2+) release, and GRP78 expression were measured.
- In vivo studies involved HT29 tumor-bearing nude mice.
Main Results:
- SiPcGlu-PDT induced apoptosis via reactive oxygen species production.
- SiPcGlu localized in lysosomes, mitochondria, and endoplasmic reticulum.
- Mitochondrial depolarization and cytochrome c release led to caspase-3 activation.
- ER Ca(2+) release and increased GRP78 expression were observed.
- SiPcGlu-PDT did not damage lysosomes but triggered apoptosis through mitochondrial and ER pathways.
- In vivo, SiPcGlu-PDT retarded tumor growth without apparent toxicity.
Conclusions:
- SiPcGlu-PDT effectively induces apoptosis in HT29 cells by targeting mitochondria and endoplasmic reticulum.
- The mechanism involves mitochondrial dysfunction and ER stress, leading to caspase-3 activation.
- SiPcGlu-PDT shows promising therapeutic potential for colorectal cancer with a favorable safety profile.
