The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance.
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 (cytochrome 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-kappaB)-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.
Chauhan
Dharminder
D
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Li
Guilan
G
Podar
Klaus
K
Hideshima
Teru
T
Shringarpure
Reshma
R
Catley
Laurence
L
Mitsiades
Constantine
C
Munshi
Nikhil
N
Tai
Yu Tzu
YT
Suh
Nanjoo
N
Gribble
Gordon W
GW
Honda
Tadashi
T
Schlossman
Robert
R
Richardson
Paul
P
Sporn
Michael B
MB
Anderson
Kenneth C
KC
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D019254:Genes, bcl-2; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D008214:Lymphocytes / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics; D009828:Oleanolic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D011480:Protease Inhibitors / Q000008:administration & dosage; D011719:Pyrazines / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D001897:Boronic Acids; D007093:Imidazoles; D015850:Interleukin-6; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D000069286:Bortezomib; D009828:Oleanolic Acid