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J. Biol. Chem., Vol. 280, Issue 43, 36273-36282, October 28, 2005

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2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) Directly Targets Mitochondrial Glutathione to Induce Apoptosis in Pancreatic Cancer^*

Ismael Samudio, Marina Konopleva, Numsen Hail, Jr., Yue-Xi Shi, Teresa McQueen, Timothy Hsu, Randall Evans, Tadashi Honda, Gordon W. Gribble, Michael Sporn¶, Hiram F. Gilbert||, Stephen Safe**, and Michael Andreeff1

From the Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, the Department of Chemistry, Dartmouth College and the ^¶Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, the ^||Department of Biochemistry, Baylor College of Medicine, Houston, Texas 77030, and the ^**Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843

Surgical resection is the only curative strategy for pancreatic cancer (PC). Unfortunately, >80% of pancreatic cancer patients bear inoperable, locally advanced, chemoresistant tumors demonstrating the urgent need for development of novel therapeutic approaches to treat this disease. Here we report that the synthetic triterpenoid 2-cyano-3,12 dioxooleana-1,9 dien-28-imidazolide (CDDO-Im) antagonizes PC cell growth by inducing apoptosis at submicromolar concentrations. Notably, we demonstrate for the first time that the cytotoxicity of CDDO-Im is accompanied by the rapid and selective depletion of mitochondrial glutathione that results in accumulation of reactive oxygen species, oxidation of the cellular glutathione pool, loss of mitochondrial membrane potential, and phosphatidylserine externalization. The parent compound CDDO as well as the methyl ester of CDDO also depleted mitochondrial glutathione, demonstrating that this effect is mediated by the triterpenoid nucleus of these agents. Cotreatment with sulfhydryl nucleophiles completely prevented apoptosis and loss of viability induced by CDDO-Im, whereas alkylation of intracellular thiols by diethylmaleate or cotreatment with dithiothreitol decreased the accumulation of a biotinylated derivative of CDDO, TP-301, in PC cells, suggesting that intracellular reduced thiols are functional targets of the electrophilic triterpenoid nucleus of CDDO and its derivatives. In conclusion, our report is the first to identify mitochondrial glutathione as a target of CDDO and its derivatives and demonstrates that depletion of this antioxidant in the mitochondria is an effective strategy to induce cell death in PC cells. These results suggest that CDDO and its derivatives may offer a clinical benefit for the treatment of PC.

Received for publication, July 12, 2005 , and in revised form, August 18, 2005.

^* This work was supported in part by National Institutes of Health Grants RO1 CA089346, PO1 CA55164, and CA16672 and the Paul and Mary Haas Chair in Genetics (to M. A.), Pancreatic Cancer Specialized Program of Research Excellence (SPORE) Grant P20 CA101936, the Leukemia and Lymphoma Society of America, the Wilson Fund for Gastrointestinal Cancer Research (to M. K.), and National Institutes of Health Grant R01 CA78814 (to M. S.). 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.

¹ To whom correspondence should be addressed: Section of Molecular Hematology and Therapy, Dept. of Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, 1400 Holcombe Blvd., Unit 448, Houston, TX 77030. Tel.: 713-792-7260; Fax: 713-794-4747; E-mail: mandreef{at}mdanderson.org.

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