Molecular Cancer Therapeutics CTRC-AACR San Antonio Breast Cancer Symposium Targeting the PI3-Kinase Pathway in Cancer
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Mol Cancer Ther. 2004;3:39-45
© 2004 American Association for Cancer Research

Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid

Takashi Ikeda1, Yukiko Nakata2, Fumihiko Kimura2, Ken Sato2, Kenneth Anderson1, Kazuo Motoyoshi2, Michael Sporn3 and Donald Kufe1

1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 2 Third Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and 3 Department of Pharmacology, Dartmouth College, Hanover, NH

Requests for Reprints: Donald W. Kufe, Dana-Farber Cancer Institute, Harvard Medical School, Dana 830, 44 Binney Street, Boston, MA 02115. Phone: (617) 632-3141; Fax: (617) 632-2934. E-mail: donald_kufe{at}dfci.harvard.edu

The synthetic oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its chemical derivatives induce differentiation and apoptosis of human leukemia cells. The precise mechanisms responsible for the effects of CDDO, however, remain unclear. In the present study, we examined the effects of CDDO and its C-28 imidazolide ester (CDDO-Im) on apoptosis of multiple myeloma (MM) cells. The results show that both CDDO and CDDO-Im are potent inducers of MM cell apoptosis and that CDDO-Im is more active than CDDO. CDDO-Im treatment was associated with (a) depletion of glutathione, (b) increases in reactive oxygen species, (c) a reduction of the Fas-associated death domain (FADD)-like interleukin-1-converting enzyme (FLICE) inhibitory protein, (d) activation of caspase-8, and (e) a decrease of the mitochondrial transmembrane potential. The reducing agents, N-acetyl-L-cysteine, DTT, and catalase inhibited each of these CDDO-Im-induced proapoptotic signals. Inhibition of caspase-8 with z-IETD-fmk also abrogated CDDO-Im-induced decreases of the mitochondrial transmembrane potential and inhibited apoptosis. These results demonstrate that CDDO-Im disrupts intracellular redox balance and thereby activates the extrinsic caspase-8-dependent apoptotic pathway. We further show that CDDO-Im induces apoptosis of primary MM cells at submicromolar concentrations and that MM cells are more sensitive to this agent than normal bone marrow mononuclear cells. These results suggest that CDDO compounds have potential as new agents for the treatment of MM.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Grant support:Grants CA42802 and CA100707 from the National Cancer Institute and by the National Foundation for Cancer Research.

Received 8/25/03; revised 10/ 7/03; accepted 10/ 9/03.




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