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Cell Growth & Differentiation Vol. 11, 261-267, May 2000
© 2000 American Association for Cancer Research

Articles

The Novel Triterpenoid 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic Acid Induces Apoptosis of Human Myeloid Leukemia Cells by a Caspase-8-dependent Mechanism1

Yasumasa Ito, Pramod Pandey, Andrew Place, Michael B. Sporn, Gordon W. Gribble, Tadashi Honda, Surender Kharbanda and Donald Kufe2

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [Y. I., P. P., S. K., D. K.], and Norris Cotton Cancer Center and Department of Pharmacology, Dartmouth Medical School [A. P., M. B. S.], Department of Chemistry, Dartmouth College [G. W. G., T. H.], Hanover, New Hampshire 03755

Abstract

The oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) is a multifunctional molecule that induces growth inhibition and differentiation of human myeloid leukemia cells. The present studies demonstrate that CDDO treatment results in apoptosis of U-937 and HL-60 myeloid leukemia cells. Similar to 1-ß-D-arabinofuranosylcytosine (ara-C), another agent that inhibits growth and induces apoptosis of these cells, CDDO induced the release of mitochondrial cytochrome c and activation of caspase-3. Overexpression of Bcl-xL blocked cytochrome c release, caspase-3 activation, and apoptosis in ara-C-treated cells. By contrast, CDDO-induced release of cytochrome c, and activation of caspase-3 were diminished only in part by Bcl-xL. In concert with these findings, we demonstrate that CDDO, but not ara-C, activates caspase-8 and thereby caspase-3 by a cytochrome c-independent mechanism. The results also show that CDDO-induced cytochrome c release is mediated by caspase-8-dependent cleavage of Bid. These findings demonstrate that CDDO induces apoptosis of myeloid leukemia cells and that this novel agent activates an apoptotic signaling cascade distinct from that induced by the cytotoxic agent ara-C.




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