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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-04-1174.
Submitted April 18, 2002
Accepted December 31, 1969
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 A Liotta, Thomas J Kipps, and John C Reed*
The Burnham Institute, La Jolla, CA, USA
Tissue Proteomics Unit, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
University of California, San Diego, La Jolla, CA, USA
University of Texas MD Anderson Cancer Center, Houston, TX, USA
ISIS Pharmaceuticals, Carlsbad, CA, USA
Darthmouth Medical School, Hanover, NH, USA
* Corresponding author; email: jreed{at}burnham.org.
Chronic Lymphocytic Leukemia (CLL) cells develop chemo-resistance over time. Most anti-cancer agents function through induction of apoptosis, and resistance against these agents is likely to be caused by selection during the treatments of CLL-cells with defects in the particular apoptosis pathway that is triggered by these compounds. Anti-cancer agents that function through alternative apoptotic pathways therefore might be useful in treating chemo-resistant CLL. Triterpenoids represent a class of naturally occurring and synthetic compounds with demonstrated anti-tumor activity. We examined the effects of triterpenoid 2-Cyano-3,12-Dioxoolean-1,9-Dien-28-Oic Acid (CDDO) 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 CrmA, a suppressor of Caspase-8, but not by 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 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. These data suggest that the synthetic triterpenoid CDDO should be explored further as a possible therapeutic agent for treatment of chemo-resistant CLL.
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