The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance

Dharminder Chauhan, Guilan Li, Klaus Podar, Teru Hideshima, Reshma Shringarpure, Laurence Catley, Constantine Mitsiades, Nikhil Munshi, Yu Tzu Tai, Nanjoo Suh, Gordon W Gribble, Tadashi Honda, Robert Schlossman, Paul Richardson, Michael B Sporn, Kenneth C Anderson

Research output: Journal article (peer-reviewed)Journal article

104 Citations (Scopus)

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 (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.

Original languageEnglish
Pages (from-to)3158-3166
Number of pages9
JournalBlood
Volume103
Issue number8
DOIs
Publication statusPublished - 15 Apr 2004
Externally publishedYes

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

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