Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
| العنوان: | Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid |
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| المؤلفون: | Takashi, Ikeda, Yukiko, Nakata, Fumihiko, Kimura, Ken, Sato, Kenneth, Anderson, Kazuo, Motoyoshi, Michael, Sporn, Donald, Kufe |
| المصدر: | Molecular Cancer Therapeutics. 3:39-45 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2004. |
| سنة النشر: | 2004 |
| مصطلحات موضوعية: | Caspase 8, Cancer Research, Dose-Response Relationship, Drug, Cell Survival, CASP8 and FADD-Like Apoptosis Regulating Protein, Imidazoles, Intracellular Signaling Peptides and Proteins, Apoptosis, Bone Marrow Cells, Intracellular Membranes, Glutathione, Antioxidants, Membrane Potentials, Mitochondria, Enzyme Activation, Oncology, Caspases, Cell Line, Tumor, Humans, Oleanolic Acid, Carrier Proteins, Multiple Myeloma, Reactive Oxygen Species, Oxidation-Reduction |
| الوصف: | The synthetic oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its chemical derivatives induce differentiation and apoptosis of human leukemia cells. The precise mechanisms responsible for the effects of CDDO, however, remain unclear. In the present study, we examined the effects of CDDO and its C-28 imidazolide ester (CDDO-Im) on apoptosis of multiple myeloma (MM) cells. The results show that both CDDO and CDDO-Im are potent inducers of MM cell apoptosis and that CDDO-Im is more active than CDDO. CDDO-Im treatment was associated with (a) depletion of glutathione, (b) increases in reactive oxygen species, (c) a reduction of the Fas-associated death domain (FADD)-like interleukin-1-converting enzyme (FLICE) inhibitory protein, (d) activation of caspase-8, and (e) a decrease of the mitochondrial transmembrane potential. The reducing agents, N-acetyl-l-cysteine, DTT, and catalase inhibited each of these CDDO-Im-induced proapoptotic signals. Inhibition of caspase-8 with z-IETD-fmk also abrogated CDDO-Im-induced decreases of the mitochondrial transmembrane potential and inhibited apoptosis. These results demonstrate that CDDO-Im disrupts intracellular redox balance and thereby activates the extrinsic caspase-8-dependent apoptotic pathway. We further show that CDDO-Im induces apoptosis of primary MM cells at submicromolar concentrations and that MM cells are more sensitive to this agent than normal bone marrow mononuclear cells. These results suggest that CDDO compounds have potential as new agents for the treatment of MM. |
| تدمد: | 1538-8514 1535-7163 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::afae9eb0215b3c847f9268ae137e4761 https://doi.org/10.1158/1535-7163.39.3.1 |
| رقم الأكسشن: | edsair.doi.dedup.....afae9eb0215b3c847f9268ae137e4761 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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