Abstract
The synthetic triterpenoid 2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid (CDDO) induces apoptosis in leukemic cells. Here we show that CDDO and its new derivative CDDO-imidazolide (CDDO-Im) trigger apoptosis in multiple myeloma (MM) cells resistant to conventional therapies including melphalan (LR-5), doxorubicin (Dox-40), and dexamethasone (MM.1R, U266, RPMI 8226) without affecting the viability of normal cells. CDDO-IM also triggers apoptosis in bone marrow stromal cells (BMSCs) and decreases interleukin-6 (IL-6) secretion induced by MM cell adhesion to BMSCs. Moreover, CDDO-Im-induced apoptosis in MM cells is not blocked by IL-6 or insulin growth factor-1 (IGF-1). Importantly, CDDO-im and bortezomib/proteasome inhibitor PS-341 trigger synergistic apoptosis in MM cells associated with loss of mitochondrial membrane potential, superoxide generation, release of mitochondrial proteins cytochrome c/second mitochondria-derived activator of caspases (cyctochrome c/Smac), and activation of caspase-8, -9, and -3. Conversely, the pancaspase inhibitor Z-VAD-fmk abrogates the CDDO-Im + bortezomib-induced apoptosis. Low doses of CDDO-Im and bortezomib overcome the cytoprotective effects of antiapoptotic proteins Bcl2 and heat shock protein-27 (Hsp27) as well as nuclear factor-kappa B (NF-κB)-mediated growth/survival and drug resistance. Finally, combining CDDO-Im and bortezomib induces apoptosis even in bortezomib-resistant MM patient cells. Together, these findings provide the framework for clinical evaluation of CDDO-Im, either alone or in combination with bortezomib, to overcome drug resistance and improve patient outcome in MM.
Original language | English |
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Pages (from-to) | 3158-3166 |
Number of pages | 9 |
Journal | Blood |
Volume | 103 |
Issue number | 8 |
DOIs | |
Publication status | Published - 15 Apr 2004 |
Externally published | Yes |
Keywords
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Apoptosis/drug effects
- Bone Marrow Cells/drug effects
- Boronic Acids/administration & dosage
- Bortezomib
- Cell Division/drug effects
- Cell Line, Tumor
- Drug Resistance, Neoplasm
- Drug Synergism
- Genes, bcl-2
- Humans
- Imidazoles/administration & dosage
- Insulin-Like Growth Factor I/pharmacology
- Interleukin-6/biosynthesis
- Lymphocytes/drug effects
- Membrane Potentials/drug effects
- Mitochondria/drug effects
- Multiple Myeloma/drug therapy
- Mutation
- NF-kappa B/genetics
- Oleanolic Acid/administration & dosage
- Protease Inhibitors/administration & dosage
- Pyrazines/administration & dosage
- Recombinant Proteins/pharmacology
- Transfection
ASJC Scopus subject areas
- Biochemistry
- Immunology
- Hematology
- Cell Biology