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Hypericin induced death receptor-mediated apoptosis in photoactivated tumor cells
Seyed Mohamed Ali1, Soo Khee Chee, Gan Yik Yuen
1Department of Medical Sciences, National Cancer Centre, School of Science, Singapore.
Abstract:
Nasopharyngeal carcinoma (NPC) is a malignant disease of the head/neck region with a 5-year survival level of approximately 65%. To explore the novel therapeutic strategies in the management of this disease, the potential effects of photodynamic therapy (PDT) in NPC cells were investigated. PDT, a new mode of treatment, is based on the combined use of light-absorbing compounds and light irradiation. Two human NPC cells such as, poorly differentiated (NPC/CNE2) and moderately differentiated (NPC/TW0-1) and other types of tumor cells like colon (CCL-220.1) and bladder (SD) undergo rapid apoptosis when treated with PDT sensitized with hypericin (HY). It has been shown that this compound has a strong photodynamic effect on tumors and viruses. However, the initiating events of PDT sensitized HY-induced apoptosis are not identified completely. In this study, we sought to determine whether Fas/FasL upregulation and involvement of mitochondrial events are an early event in HY-treated PDT induced apoptosis. Loss of mitochondrial transmembrane potential, release of cytochrome c, involvement of caspases 8 and 3 and the status caspase-3 specific substrate PARP, were evaluated in PDT treated tumor cells. Photosensitization of HY enhanced both CD95/CD95L expression and induced CD95-signaling dependent cell death in all tumor cell lines studied. CD95/CD95L expression appeared within 2 h following light irradiation and appeared to be a principal event in PDT induced apoptosis. Furthermore, these results indicate that release of mitochondrial cytochrome c into the cytoplasm within 2-3 h post PDT is a secondary event following the activation of initiator caspase-8 preceding Apaf-1, caspase-9 and caspase-3 activation, cleavage of PARP and DNA fragmentation.
Insights
Photodynamic therapy (PDT) with hypericin (HY) induces apoptosis in nasopharyngeal carcinoma (NPC) and other tumor cells. This PDT treatment primarily involves Fas/FasL upregulation, a key event preceding mitochondrial pathway activation.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Nasopharyngeal carcinoma (NPC) is a head and neck cancer with a 5-year survival rate of approximately 65%.
- Photodynamic therapy (PDT) is an emerging treatment modality utilizing photosensitizers and light to induce cancer cell death.
- Hypericin (HY) is a photosensitizer known for its photodynamic effects on tumors and viruses, but its precise role in inducing apoptosis requires further elucidation.
Purpose of the Study:
- To investigate the early molecular events in hypericin-sensitized photodynamic therapy (HY-PDT)-induced apoptosis in nasopharyngeal carcinoma (NPC) and other tumor cells.
- To determine the involvement of the Fas/FasL pathway and mitochondrial events in HY-PDT-induced apoptosis.
Main Methods:
- Treatment of human NPC cell lines (NPC/CNE2, NPC/TW0-1) and other tumor cells (colon CCL-220.1, bladder SD) with HY-PDT.
- Evaluation of Fas/FasL (CD95/CD95L) expression, mitochondrial transmembrane potential, cytochrome c release, caspase activation (caspase-8, -3), PARP cleavage, and DNA fragmentation.
Main Results:
- HY-PDT induced rapid apoptosis in all tested tumor cell lines.
- Fas/FasL (CD95/CD95L) expression was upregulated within 2 hours post-irradiation, indicating its role as an early event in HY-PDT-induced apoptosis.
- Mitochondrial cytochrome c release occurred 2-3 hours post-PDT, following caspase-8 activation, suggesting it is a secondary event in the apoptotic cascade.
Conclusions:
- Fas/FasL upregulation is a principal initiating event in HY-PDT-induced apoptosis in NPC and other tumor cells.
- Mitochondrial events, including cytochrome c release and caspase activation, are downstream of the initial Fas/FasL signaling in this context.
- HY-PDT represents a promising therapeutic strategy for NPC, with its mechanism involving the extrinsic apoptotic pathway.