Apoptosis induced by intracellular ceramide accumulation in MDA-MB-435 breast carcinoma cells is dependent on the generation of reactive oxygen species

Strategies to promote intracellular ceramide accumulation in cancer cells may have therapeutic utility because ceramide is an important second messenger during apoptosis. Exposure to cell-permeable C 6 ceramide or tricyclodecan-9-yl-xanthate (an inducer of de novo ceramide synthesis and an inhibitor...

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Published in:Experimental and molecular pathology 2007-02, Vol.82 (1), p.1-11
Main Authors: Chan, S.Y. Velda, Hilchie, Ashley L., Brown, Michael G., Anderson, Robert, Hoskin, David W.
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis - drug effects
Apoptosis - physiology
Biological and medical sciences
Breast cancer
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell Line, Tumor
Ceramidase
Ceramide
Ceramides - antagonists & inhibitors
Ceramides - metabolism
DNA Fragmentation - drug effects
Enzyme Inhibitors - pharmacology
Female
Glucosylceramide synthase
Gynecology. Andrology. Obstetrics
Humans
Investigative techniques, diagnostic techniques (general aspects)
Mammary gland diseases
Medical sciences
Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
Reactive oxygen species
Reactive Oxygen Species - metabolism
Tumors
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Summary:Strategies to promote intracellular ceramide accumulation in cancer cells may have therapeutic utility because ceramide is an important second messenger during apoptosis. Exposure to cell-permeable C 6 ceramide or tricyclodecan-9-yl-xanthate (an inducer of de novo ceramide synthesis and an inhibitor of sphingomyelin synthase) caused MDA-MB-435 human breast carcinoma cells to die by apoptosis. Concomitant treatment with the ceramidase inhibitor d- erythro-2-( N-myristoylamino)-1-phenyl-1-propanol (MAPP) or the glucosylceramide synthase inhibitor 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) potentiated the cytotoxic effect of C 6 ceramide, indicating that C 6 ceramide-mediated cytotoxicity was antagonized by the action of ceramidases and glucosylceramide synthase. Interestingly, treatment with PPMP alone, but not MAPP alone, also induced apoptosis in MDA-MB-435 cells, suggesting that conversion to glucosylceramide rather than catabolism by ceramidases prevented endogenous ceramide from reaching cytotoxic levels. C 6 ceramide-induced apoptosis in MDA-MB-435 cells was associated with the generation of reactive oxygen species, and was inhibited by the antioxidants N-acetylcysteine and glutathione. Although mitochondrial membrane integrity was disrupted in C 6 ceramide-treated MDA-MB-435 cells, apoptosis was not mediated by caspases because there was no protective effect by the pan-caspase inhibitor z-VAD-fmk. Collectively, these findings indicate that strategies to enhance intracellular ceramide accumulation in malignant cells might offer a novel approach to the treatment of breast cancer.
ISSN:0014-4800
1096-0945
DOI:10.1016/j.yexmp.2006.03.001