Recent studies have described a biochemical pathway whereby lysosome disruption and the released proteases initiate the intrinsic apoptotic pathway. Irradiation of murine hepatoma 1c1c7 cells preloaded with the lysosomal photosensitizer NPe6 (N-aspartyl chlorin e6) caused a rapid loss of Acridine Orange staining of acidic organelles, release of cathepsin D from late endosomes/lysosomes and the activation of procaspase-3. Pretreatment of NPe6-loaded cultures with 10–50 μM 3-O-MeSM (3-O-methylsphingomyelin) caused a concentration-dependent suppression of apoptosis following irradiation. This suppression reflected a stabilization of lysosomes/endosomes, as opposed to an inhibition of the accumulation of photosensitizer in these organelles. Exogenously added sphingomyelin, at comparable concentrations, offered some protection, but less than 3-O-MeSM. Fluorescence microscopy showed that 3-O-MeSM competed with NBD-C6-sphingomyelin (6-{[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]hexanoyl} sphingosyl phosphocholine) for co-localization with LysoTracker Red in acidic organelles. Pre-treatment of 1c1c7 cultures with 3-O-MeSM also suppressed the induction of apoptosis by TNFα (tumour necrosis factor α), but offered no protection against HA14-1 [ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate], staurosporine, tunicamycin or thapsigargin. These results suggest that exogenously added 3-O-MeSM is trafficked to and stabilizes late endosomes/lysosomes against oxidant-induced damage, and further implicate a role for lysosomal proteases in the apoptotic processes initiated by TNFα and lysosomal photosensitizers.
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Research Article|
November 22 2005
Sphingomyelins suppress the targeted disruption of lysosomes/endosomes by the photosensitizer NPe6 during photodynamic therapy
Joseph A. Caruso;
Joseph A. Caruso
1Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48201, U.S.A.
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Patricia A. Mathieu;
Patricia A. Mathieu
1Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48201, U.S.A.
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John J. Reiners, Jr
John J. Reiners, Jr
1
1Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48201, U.S.A.
1To whom correspondence should be addressed (email john.reiners.jr@wayne.edu).
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Publisher: Portland Press Ltd
Received:
February 18 2005
Revision Received:
May 20 2005
Accepted:
June 08 2005
Accepted Manuscript online:
June 08 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 392 (2): 325–334.
Article history
Received:
February 18 2005
Revision Received:
May 20 2005
Accepted:
June 08 2005
Accepted Manuscript online:
June 08 2005
Citation
Joseph A. Caruso, Patricia A. Mathieu, John J. Reiners; Sphingomyelins suppress the targeted disruption of lysosomes/endosomes by the photosensitizer NPe6 during photodynamic therapy. Biochem J 1 December 2005; 392 (2): 325–334. doi: https://doi.org/10.1042/BJ20050313
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