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Blood, 15 April 2004, Vol. 103, No. 8, pp. 3158-3166. Prepublished online as a Blood First Edition Paper on December 11, 2003; DOI 10.1182/blood-2003-08-2873. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-08-2873v1 103/8/3158    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chauhan, D. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Chauhan, D. Articles by Anderson, K. C. Related Collections Apoptosis Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA 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, and Kenneth C. Anderson From the Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Department of Chemistry, Dartmouth College, Hanover, NH; and Department of Pharmacology, Dartmouth Medical School, Hanover, NH. 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 proteinscytochrome 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-B)–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. (Blood. 2004;103: 3158-3166) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Ahmad, D. Raina, C. Meyer, and D. 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