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Arsenic trioxide (ATO) induces apoptosis in a range of solid tumors and leukemia cells, and has been clinically applied for the treatment of acute promyelocytic leukemia with confirmed efficacy. Acute megakaryocytic leukemia (AMKL) is an aggressive malignancy with poor prognosis, if bone marrow transplantation is not possible. In this study, we applied flow cytometry, Western blot analysis and microarray techniques to investigate the effects of ATO on apoptosis and the cell division cycle of AMKL cell lines CHRF-288-11 and MEG-01. Our data demonstrated that ATO is a potent agent against AMKL as indicated by apoptotic markers, Annexin V and caspase-3. ATO activated the intrinsic (mitochondrial) pathway of apoptosis, which involved disrupting mitochondrial membrane potential, increased Bax/Bcl-2 ratio and caspase-9 activation, as well as the extrinsic (death receptor) pathway mediated by Fas and caspase-8 activation. We provided the first evidence that ATO stimulated expressions of CD137 mRNA and protein, which might be relevant to the extrinsic mechanism. ATO induced delays of cell cycle progression at S phase and arrest at G2/M phase of AMKL cells, but caspase-3 expression appeared not to be phase-specific. The multiple-signaling mechanism of ATO warrants it a potential agent to incorporate in the treatment regimen of AMKL.

Type

Journal article

Journal

Int J Oncol

Publication Date

08/2005

Volume

27

Pages

537 - 545

Keywords

Antigens, CD, Apoptosis, Arsenicals, Caspase 8, Caspase 9, Caspases, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Dose-Response Relationship, Drug, Flow Cytometry, Gene Expression Regulation, Neoplastic, Humans, Intracellular Membranes, Leukemia, Megakaryoblastic, Acute, Membrane Potentials, Mitochondria, Oligonucleotide Array Sequence Analysis, Oxides, Proto-Oncogene Proteins c-bcl-2, RNA, Messenger, Receptors, Cell Surface, Receptors, Nerve Growth Factor, Receptors, Tumor Necrosis Factor, Signal Transduction, Time Factors, Tumor Necrosis Factor Receptor Superfamily, Member 9, fas Receptor