期刊
BIOCHEMICAL PHARMACOLOGY
卷 81, 期 5, 页码 606-616出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2010.12.015
关键词
Photodynamic therapy; NF-kappa B; Glioblastoma; Necrosis; Autophagy; Apoptosis
资金
- FRIA (Brussels, Belgium)
- F.R.S.-FNRS [F/5/4/5-MCF/KP]
- FNRS
- Inter-University Attraction Poles, Brussels, Belgium [IAP6/18]
- K.U. Leuven [OT/06/49]
Glioblastoma constitute the most frequent and deadliest brain tumors of astrocytic origin. They are very resistant to all current therapies and are associated with a huge rate of recurrence. In most cases, this type of tumor is characterized by a constitutive activation of the nuclear factor-kappaB (NF-kappa B). This factor is known to be a key regulator of various physiological processes such as inflammation, immune response, cell growth or apoptosis. In the present study, we explored the role of NF-kappa B activation in the sensitivity of human glioblastoma cells to a treatment by 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT). 5-ALA is a physiological compound widely used in PDT as well as in tumor photodetection (POD). Our results show that inhibition of NF-kappa B improves glioblastoma cell death in response to 5-ALA-PDT. We then studied the molecular mechanisms underlying the cell death induced by PDT combined or not with NF-kappa B inhibition. We found that apoptosis was induced by PDT but in an incomplete manner and that, unexpectedly, NF-kappa B inhibition reduced its level. Oppositely PDT mainly induces necrosis in glioblastoma cells and NF-kappa B is found to have anti-necrotic functions in this context. The autophagic flux was also enhanced as a result of 5-ALA-PDT and we demonstrate that stimulation of autophagy acts as a pro-survival mechanism confering protection against PDT-mediated necrosis. These data point out that 5-ALA-PDT has an interesting potential as a mean to treat glioblastoma and that inhibition of NF-kappa B renders glioblastoma cells more sensitive to the treatment. (C) 2010 Elsevier Inc. All rights reserved.
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