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Prepublished online as a Blood First Edition Paper on January 16, 2003; DOI 10.1182/blood-2002-10-3231. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-10-3231v1 101/10/4078    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 Liu, Q. Articles by Gazitt, Y. Search for Related Content PubMed PubMed Citation Articles by Liu, Q. Articles by Gazitt, Y. Related Collections Neoplasia Apoptosis Cell Cycle Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 May 2003, Vol. 101, No. 10, pp. 4078-4087 NEOPLASIA Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL Qun Liu, Susan Hilsenbeck, and Yair Gazitt From the University of Texas Health Science Center, San Antonio; and Breast Center, Baylor College of Medicine, Houston, TX. Arsenic trioxide (ATO) has been shown to induce differentiation and apoptosis in acute promyelocytic leukemia (APL) cells concomitant with down-regulation of the PML-RAR fusion protein, a product of the t(15:17) translocation characteristic of APL leukemic cells. However, ATO is also a potent inducer of apoptosis in a number of other cancer cells lacking the t(15:17) translocation. The exact mechanism of ATO-induced apoptosis in these cells is not yet clear. We tested the effect of ATO on 7 myeloma cell lines with varying p53 status and report that in cells with mutated p53, ATO induced rapid and extensive (more than 90%) apoptosis in a time- and dose-dependent manner concomitant with arrest of cells in G2/M phase of the cell cycle. Myeloma cells with wild-type (wt) p53 were relatively resistant to ATO with maximal apoptosis of about 40% concomitant with partial arrest of cells in G1 and up-regulation of p21. The use of caspase blocking peptides, fluorescence-tagged caspase-specific substrate peptides, and Western immunoblotting confirmed the involvement of primarily caspase-8 and -3 in ATO-induced apoptosis in myeloma cells with mutated p53 and primarily caspase-9 and -3 in cells expressing wt p53. We also observed up-regulation by ATO of R1 and R2 APO2/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) receptors. Most important, however, we observed a synergy between ATO and APO2/TRAIL in the induction of apoptosis in the partially resistant myeloma cell lines and in myeloma cells freshly isolated from myeloma patients. Our results justify the use of the combination of these 2 drugs in clinical setting in myeloma patients. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. A. Morales, D. Gutman, K. P. Lee, and L. H. Boise BH3-only proteins Noxa, Bmf, and Bim are necessary for arsenic trioxide-induced cell death in myeloma Blood, May 15, 2008; 111(10): 5152 - 5162. [Abstract] [Full Text] [PDF] Y. H. Han, S. Z. Kim, S. H. Kim, and W. H. Park Arsenic trioxide inhibits growth of As4.1 juxtaglomerular cells via cell cycle arrest and caspase-independent apoptosis Am J Physiol Renal Physiol, August 1, 2007; 293(2): F511 - F520. [Abstract] [Full Text] [PDF] D. 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