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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 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 Citation Map 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. Related Collections Apoptosis Oncogenes and Tumor Suppressors Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA 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 From the Department of Pediatrics and the Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan; the Department of Pathology and Host Defense, Kagawa Medical University, Kagawa, Japan; the Biomolecular Science Center, Molecular Biology and Microbiology, University of Central Florida, Orlando, FL; and the Centre National de la Recherche Scientifique, UMR 8125, Institut Gustave Roussy, Villejuif, France. 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: F. Huguet, N. Giocanti, C. Hennequin, M. Croisy, E. Touboul, and V. Favaudon Growth inhibition by STI571 in combination with radiation in human chronic myelogenous leukemia K562 cells Mol. Cancer Ther., February 1, 2008; 7(2): 398 - 406. [Abstract] [Full Text] [PDF] L. Li, W. Han, Y. Gu, S. Qiu, Q. Lu, J. Jin, J. Luo, and X. Hu Honokiol Induces a Necrotic Cell Death through the Mitochondrial Permeability Transition Pore Cancer Res., May 15, 2007; 67(10): 4894 - 4903. [Abstract] [Full Text] [PDF] X. D. Zhang, J. J. Wu, S. Gillespie, J. Borrow, and P. Hersey Human Melanoma Cells Selected for Resistance to Apoptosis by Prolonged Exposure to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Are More Vulnerable to Necrotic Cell Death Induced by Cisplatin Clin. Cancer Res., February 15, 2006; 12(4): 1355 - 1364. [Abstract] [Full Text] [PDF] K. Ishitsuka, T. Hideshima, M. Hamasaki, N. Raje, S. Kumar, H. Hideshima, N. Shiraishi, H. Yasui, A. M. Roccaro, P. Richardson, et al. Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis Blood, September 1, 2005; 106(5): 1794 - 1800. [Abstract] [Full Text] [PDF]

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