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Blood, 15 March 2004, Vol. 103, No. 6, pp. 2299-2307. Prepublished online as a Blood First Edition Paper on November 26, 2003; DOI 10.1182/blood-2003-05-1605. This Article Full Text (PDF) All Versions of this Article: 2003-05-1605v1 103/6/2299    most recent Alert me when this article is cited Alert me if a correction is posted 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 Okada, M. Articles by Nakahata, T. Search for Related Content PubMed PubMed Citation Articles by Okada, M. Articles by Nakahata, T. Social Bookmarking                   What's this? Submitted May 20, 2003 Accepted October 31, 2003 A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL-positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity Masayuki Okada, Souichi Adachi*, Tsuyoshi Imai, Ken-ichiro Watanabe, Shin-ya Toyokuni, Masaki Ueno, Antonis S Zervos, Guido Kroemer, and Tatsutoshi Nakahata Department of Pediatrics, Kyoto University, Kyoto, Japan Department of Pathology and Biology of Diseases, Kyoto University, Kyoto, Japan Department of Pathology and Host Defense, Kagawa Medical University, Kagawa, Japan Biomolecular Science Center, Molecular Biology and Microbiology, University of Central Florida, Orlando, FL, USA Centre National de la Recherche Scientifique, UMR 8125, Institut Gustave Roussy, Villejuif, France * Corresponding author; email: sadachi{at}kuhp.kyoto-u.ac.jp. Caspase-independent programmed cell death can exhibit either an apoptosis-like or a necrosis-like morphology. The ABL kinase inhibitor, imatinib mesylate, has been reported to induce apoptosis of BCR-ABL positive cells in a caspase-dependent fashion. We investigated whether caspases alone were the mediators of imatinib mesylate-induced cell death. In contrast to previous reports, we found that a broad caspase inhibitor, zVAD-fmk, failed to prevent the death of imatinib mesylate-treated BCR-ABL positive human leukemic cells. Moreover, zVAD-fmk-preincubated, imatinib mesylate-treated cells exhibited a necrosis-like morphology characterized by cellular pyknosis, cytoplasmic vacuolization, and the absence of nuclear signs of apoptosis. These cells manifested a loss of the mitochondrial transmembrane potential, indicating the mitochondrial involvement in this caspase-independent necrosis. We excluded the participation of several mitochondrial factors possibly involved in caspase-independent cell death such as apoptosis-inducing factor, endonuclease G, and reactive oxygen species. However, we observed the mitochondrial release of the serine protease Omi/HtrA2 into the cytosol of the cells treated with imatinib mesylate or zVAD-fmk plus imatinib mesylate. Furthermore, serine protease inhibitors prevented the caspase-independent necrosis. Taken together, our results suggest that imatinib mesylate induces a caspase-independent, necrosis-like programmed cell death mediated by the serine protease activity of Omi/HtrA2. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Kravchenko-Balasha, S. Mizrachy-Schwartz, S. Klein, and A. Levitzki Shift from Apoptotic to Necrotic Cell Death during Human Papillomavirus-induced Transformation of Keratinocytes J. Biol. 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