1: Blood. 2003 Dec 11 [Epub ahead of print]. Related Articles, Links
Bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance.
Chauhan D, Li G, Podar K, Hideshima T, Shringarpure R, Catley L, Mitsiades C, Munshi N, Tai YT, Suh N, Gribble GW, Honda T, Schlossman R, Richardson P, Sporn MB, Anderson KC.
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
The synthetic triterpenoid 2-cyano-3, 12-dioxoolean-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 (LR5), 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/Smac, and activation of caspase-8/9/3. Conversely, the pan caspase inhibitor Z-VAD-fmk abrogates the CDDO-Im + Bortezomib-induced apoptosis. Low doses of CDDO-Im and Bortezomib overcomes the cytoprotective effects of anti-apoptotic proteins Bcl2 and Hsp27, as well as NF-kB-mediated growth/survival, and drug-resistance. Finally, combining CDDO-Im and Bortezomib induces apoptosis even in Bortezomib-resistance 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. |
