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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-04-1174. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-04-1174v1 100/8/2965    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 Pedersen, I. M. Articles by Reed, J. C. Search for Related Content PubMed PubMed Citation Articles by Pedersen, I. M. Articles by Reed, J. C. Related Collections Neoplasia Apoptosis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 October 2002, Vol. 100, No. 8, pp. 2965-2972 NEOPLASIA The triterpenoid CDDO induces apoptosis in refractory CLL B cells Irene M. Pedersen, Shinichi Kitada, Aaron Schimmer, Youngsoo Kim, Juan M. Zapata, Lula Charboneau, Laura Rassenti, Michael Andreeff, Frank Bennett, Michael B. Sporn, Lance D. Liotta, Thomas J. Kipps, and John C. Reed From The Burnham Institute and University of California-San Diego, La Jolla, CA; Tissue Proteomics Unit, National Cancer Institute, National Institutes of Health, Bethesda, MD; The University of Texas MD Anderson Cancer Center, Houston; ISIS Pharmaceuticals, Carlsbad, CA; and Dartmouth Medical School, Hanover, NH. Chronic lymphocytic leukemia (CLL) cells develop chemo-resistance over time. Most anticancer agents function through induction of apoptosis, and therefore resistance against these agents is likely to be caused by selection for CLL cells with defects in the particular apoptosis pathway that is triggered by these drugs. Anticancer agents that function through alternative apoptotic pathways might therefore be useful in treating chemo-resistant CLL. Triterpenoids represent a class of naturally occurring and synthetic compounds with demonstrated antitumor activity. We examined the effects of CDDO (triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid) on CLL B cells in vitro. CDDO induced apoptosis in a dose-dependent manner in all (n = 30) CLL samples tested, including previously untreated and chemo-resistant CLL specimens. CDDO induced rapid proteolytic processing of caspase-8, but not caspase-9, in CLL B cells, suggesting activation of a mitochondria-independent pathway. CDDO-induced apoptosis of CLL B cells was blocked by cytokine response modifier A (CrmA), a suppressor of caspase-8, but not by X-linked inhibitor of apoptosis protein-baculovirus IAP repeat-3 (XIAP-BIR3), a fragment of XIAP, which selectively inhibits caspase-9. Examination of CDDO effects on expression of several apoptosis-relevant genes demonstrated significant reductions in the levels of caspase-8 homolog Fas-ligand interleukin-1-converting enzyme (FLICE)-inhibitory protein (c-FLIP), an endogenous antagonist of caspase-8. However, reductions of FLIP achieved by FLIP antisense oligonucleotides were insufficient for triggering apoptosis, indicating that CDDO has other targets in CLL B cells besides FLIP. 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	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020