Abstract |
Our study has shown that the Amaryllidaceae isocarbostyril narciclasine induces marked apoptosis-mediated cytotoxic effects in human cancer cells but not in normal fibroblasts by triggering the activation of the initiator caspases of the death receptor pathway (caspase-8 and caspase-10) at least in human MCF-7 breast and PC-3 prostate carcinoma cells. The formation of the Fas and death receptor 4 (DR4) death-inducing signaling complex was clearly evidenced in MCF-7 and PC-3 cancer cells. Caspase-8 was found to interact with Fas and DR4 receptors on narciclasine treatment. However, narciclasine-induced downstream apoptotic pathways in MCF-7 cells diverged from those in PC-3 cells, where caspase-8 directly activated effector caspases such as caspase-3 in the absence of any further release of mitochondrial proapoptotic effectors. In contrast, in MCF-7 cells, the apoptotic process was found to require an amplification step that is mitochondria-dependent, with Bid processing, release of cytochrome c, and caspase-9 activation. It is postulated that the high selectivity of narciclasine to cancer cells might be linked, at least in part, to this activation of the death receptor pathway. Normal human fibroblasts appear approximately 250-fold less sensitive to narciclasine, which does not induce apoptosis in these cells probably due to the absence of death receptor pathway activation.
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Authors | Patrick Dumont, Laurent Ingrassia, Sébastien Rouzeau, Fabrice Ribaucour, Stéphanie Thomas, Isabelle Roland, Francis Darro, Florence Lefranc, Robert Kiss |
Journal | Neoplasia (New York, N.Y.)
(Neoplasia)
Vol. 9
Issue 9
Pg. 766-76
(Sep 2007)
ISSN: 1476-5586 [Electronic] United States |
PMID | 17898872
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amaryllidaceae Alkaloids
- Antineoplastic Agents, Phytogenic
- BH3 Interacting Domain Death Agonist Protein
- BID protein, human
- Neoplasm Proteins
- Phenanthridines
- Receptors, TNF-Related Apoptosis-Inducing Ligand
- Receptors, Tumor Necrosis Factor
- TNFRSF10A protein, human
- fas Receptor
- narciclasine
- Cytochromes c
- Caspases
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Topics |
- Amaryllidaceae Alkaloids
(isolation & purification, pharmacology)
- Antineoplastic Agents, Phytogenic
(isolation & purification, pharmacology)
- Apoptosis
(drug effects, physiology)
- BH3 Interacting Domain Death Agonist Protein
(physiology)
- Breast Neoplasms
(metabolism, pathology)
- Carcinoma
(metabolism, pathology)
- Caspases
(physiology)
- Cytochromes c
(analysis)
- DNA Fragmentation
- Drug Resistance, Neoplasm
- Enzyme Activation
(drug effects)
- Female
- Fibroblasts
(drug effects)
- Humans
- Male
- Mitochondria
(enzymology, physiology)
- Narcissus
(chemistry)
- Neoplasm Proteins
(drug effects, physiology)
- Phenanthridines
(isolation & purification, pharmacology)
- Prostatic Neoplasms
(metabolism, pathology)
- Receptors, TNF-Related Apoptosis-Inducing Ligand
- Receptors, Tumor Necrosis Factor
(physiology)
- fas Receptor
(drug effects, physiology)
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