Title

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

Authors

Authors

M. Okada; S. Adachi; T. Imai; K. Watanabe; S. Y. Toyokuni; M. Ueno; A. S. Zervos; G. Kroemer;T. Nakahata

Comments

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Abbreviated Journal Title

Blood

Keywords

CHRONIC MYELOGENOUS LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; ACUTE; LYMPHOBLASTIC-LEUKEMIA; NECROTIC TUMOR-CELLS; TYROSINE KINASE; PHILADELPHIA-CHROMOSOME; CYTOGENETIC RESPONSES; APOPTOTIC CELLS; DENDRITIC CELLS; BLAST CRISIS; Hematology

Abstract

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. (C) 2004 by The American Society of Hematology.

Journal Title

Blood

Volume

103

Issue/Number

6

Publication Date

1-1-2004

Document Type

Article

Language

English

First Page

2299

Last Page

2307

WOS Identifier

WOS:000220123400050

ISSN

0006-4971

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