The Amaryllidaceae Isocarbostyril Narciclasine Induces Apoptosis By Activation of the Death Receptor and/or Mitochondrial Pathways in Cancer Cells But Not in Normal Fibroblasts
Copyright policy )The Amaryllidaceae Isocarbostyril Narciclasine Induces Apoptosis By Activation of the Death Receptor and/or Mitochondrial Pathways in Cancer Cells But Not in Normal Fibroblasts
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.
- Erasmus Hospital Belgium
- Université Catholique de Louvain Belgium
- Université Libre de Bruxelles Belgium
BH3 Interacting Domain Death Agonist Protein - physiology, Male, Caspases -- physiology, Phytogenic -- pharmacology, Drug Resistance, Prostatic Neoplasms -- metabolism, Apoptosis, Neoplasm Proteins -- physiology, Fibroblasts - drug effects, Carcinoma -- metabolism, Neoplasm Proteins - drug effects, physiology, CD95 -- physiology, BH3 Interacting Domain Death Agonist Protein -- physiology, Receptors, Carcinoma -- pathology, Amaryllidaceae Alkaloids -- pharmacology, CD95 -- drug effects, Narcissus -- chemistry, RC254-282, Prostatic Neoplasms -- pathology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cytochromes c, Narcissus, Enzyme Activation -- drug effects, Sciences bio-médicales et agricoles, Receptors, Tumor Necrosis Factor - physiology, Mitochondria, Neoplasm Proteins, Phenanthridines, Caspases, Breast Neoplasms -- pathology, Female, Phytogenic -- isolation & purification, Carcinoma - metabolism, pathology, Narcissus - chemistry, BH3 Interacting Domain Death Agonist Protein, Enzyme Activation - drug effects, Amaryllidaceae Alkaloids -- isolation & purification, Antineoplastic Agents, Breast Neoplasms, DNA Fragmentation, Breast Neoplasms -- metabolism, Prostatic Neoplasms - metabolism, pathology, Phenanthridines -- isolation & purification, fibroblasts, Mitochondria -- enzymology, Humans, Antigens, Cytochromes c -- analysis, Breast Neoplasms - metabolism, pathology, Neoplasm Proteins -- drug effects, Phenanthridines - isolation & purification, pharmacology, Fibroblasts -- drug effects, Mitochondria -- physiology, Antineoplastic Agents, Phytogenic - isolation & purification, pharmacology, Carcinoma, Apoptosis -- physiology, Antigens, CD95 - drug effects, physiology, Prostatic Neoplasms, Amaryllidaceae Alkaloids - isolation & purification, pharmacology, death receptor pathway, Fibroblasts, Antineoplastic Agents, Phytogenic, Apoptosis - drug effects, physiology, Enzyme Activation, Phenanthridines -- pharmacology, Tumor Necrosis Factor -- physiology, Drug Resistance, Neoplasm, Caspases - physiology, cancer cells, Amaryllidaceae Alkaloids, Neoplasm, Mitochondria - enzymology, physiology, Apoptosis -- drug effects, Cytochromes c - analysis, narciclasine
BH3 Interacting Domain Death Agonist Protein - physiology, Male, Caspases -- physiology, Phytogenic -- pharmacology, Drug Resistance, Prostatic Neoplasms -- metabolism, Apoptosis, Neoplasm Proteins -- physiology, Fibroblasts - drug effects, Carcinoma -- metabolism, Neoplasm Proteins - drug effects, physiology, CD95 -- physiology, BH3 Interacting Domain Death Agonist Protein -- physiology, Receptors, Carcinoma -- pathology, Amaryllidaceae Alkaloids -- pharmacology, CD95 -- drug effects, Narcissus -- chemistry, RC254-282, Prostatic Neoplasms -- pathology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cytochromes c, Narcissus, Enzyme Activation -- drug effects, Sciences bio-médicales et agricoles, Receptors, Tumor Necrosis Factor - physiology, Mitochondria, Neoplasm Proteins, Phenanthridines, Caspases, Breast Neoplasms -- pathology, Female, Phytogenic -- isolation & purification, Carcinoma - metabolism, pathology, Narcissus - chemistry, BH3 Interacting Domain Death Agonist Protein, Enzyme Activation - drug effects, Amaryllidaceae Alkaloids -- isolation & purification, Antineoplastic Agents, Breast Neoplasms, DNA Fragmentation, Breast Neoplasms -- metabolism, Prostatic Neoplasms - metabolism, pathology, Phenanthridines -- isolation & purification, fibroblasts, Mitochondria -- enzymology, Humans, Antigens, Cytochromes c -- analysis, Breast Neoplasms - metabolism, pathology, Neoplasm Proteins -- drug effects, Phenanthridines - isolation & purification, pharmacology, Fibroblasts -- drug effects, Mitochondria -- physiology, Antineoplastic Agents, Phytogenic - isolation & purification, pharmacology, Carcinoma, Apoptosis -- physiology, Antigens, CD95 - drug effects, physiology, Prostatic Neoplasms, Amaryllidaceae Alkaloids - isolation & purification, pharmacology, death receptor pathway, Fibroblasts, Antineoplastic Agents, Phytogenic, Apoptosis - drug effects, physiology, Enzyme Activation, Phenanthridines -- pharmacology, Tumor Necrosis Factor -- physiology, Drug Resistance, Neoplasm, Caspases - physiology, cancer cells, Amaryllidaceae Alkaloids, Neoplasm, Mitochondria - enzymology, physiology, Apoptosis -- drug effects, Cytochromes c - analysis, narciclasine
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