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As2O3 exerts dose-dependent dual effects on APL cells GQ Chen, XG Shi, W Tang, SM Xiong, J Zhu, X Cai, ZG Han, JH Ni, GY Shi, PM Jia, MM Liu, KL He, C Niu, J Ma, P Zhang, TD Zhang, P Paul, T Naoe, K Kitamura, W Miller, S Waxman, ZY Wang, H de The, SJ Chen and Z Chen Shanghai Institute of Hematology, Samuel Waxman Cancer Research Foundation Lab, Rui-Jin Hospital, China. Recent clinical studies in China showed that As2O3 is an effective and relatively safe drug in the treatment of acute promyelocytic leukemia (APL). We found previously that As2O3 can trigger apoptosis of APL cell line NB4 cells, which is associated with downregulation of bcl-2 gene expression and modulation of PML-RAR alpha chimeric protein. To further understand the mechanisms of this alternative therapy for APL, we investigated in this report the effects of a wide range of concentrations of As2O2 on cultured primary APL cells, all-trans retinoic acid (ATRA)-susceptible (NB4 cells) and ATRA-resistant (MR2 subclone) APL cell lines. The results indicated that As2O3 had dose- dependent dual effects on APL cells: inducing preferentially apoptosis at relatively high concentrations (0.5 to 2 micromol/L) and inducing partial differentiation at low concentrations (0.1 to 0.5 micromol/L). The rapid modulation and degradation of PML-RAR alpha proteins, which was induced by As2O3 at 0.1 to 2 micromol/L, could contribute to these two effects. Bone marrow and peripheral blood examination showed that myelocyte-like cells, probably as a result of partial in vivo differentiation, and degenerative cells increased after 2 to 3 weeks of continuous in vivo As2O3 treatment when leukemic promyelocytes decreased. In conclusion, combination of induction of apoptosis and partial differention could be the main cellular mechanisms of As2O3 in the treatment of APL, and PML-RAR alpha could play an important role in determining the specific effects of As2O3 on APL cells. Volume 89, Issue 9, pp. 3345-3353, 05/01/1997 Copyright © 1997 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: C.-J. Yao, C.-M. Yang, S.-E. Chuang, J.-L. Yan, C.-Y. Liu, S.-W. Chen, K.-H. Yan, T.-Y. Lai, and G.-M. Lai Targeting PML-RAR{alpha} and Oncogenic Signaling Pathways by Chinese Herbal Mixture Tien-Hsien Liquid in Acute Promyelocytic Leukemia NB4 Cells Evid. Based Complement. Altern. Med., November 23, 2009; (2009) nep165v2. [Abstract] [Full Text] [PDF] R. Nasr, V. Lallemand-Breitenbach, J. Zhu, M.-C. Guillemin, and H. de The Therapy-induced PML/RARA Proteolysis and Acute Promyelocytic Leukemia Cure Clin. 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M.E. Chalmers-Redman, W. G. Tatton, and S. Waxman Arsenic Trioxide Selectively Induces Acute Promyelocytic Leukemia Cell Apoptosis Via a Hydrogen Peroxide-Dependent Pathway Blood, September 15, 1999; 94(6): 2102 - 2111. [Abstract] [Full Text] [PDF] T. Sternsdorf, E. Puccetti, K. Jensen, D. Hoelzer, H. Will, O. G. Ottmann, and M. Ruthardt PIC-1/SUMO-1-Modified PML-Retinoic Acid Receptor alpha  Mediates Arsenic Trioxide-Induced Apoptosis in Acute Promyelocytic Leukemia Mol. Cell. Biol., July 1, 1999; 19(7): 5170 - 5178. [Abstract] [Full Text] [PDF] C. Huang, W.-y. Ma, J. Li, and Z. Dong Arsenic Induces Apoptosis through a c-Jun NH2-Terminal Kinase-dependent, p53-independent Pathway Cancer Res., July 1, 1999; 59(13): 3053 - 3058. [Abstract] [Full Text] [PDF] J.-R. Gurr, D.-T. Bau, F. Liu, S. Lynn, and K.-Y. Jan Dithiothreitol Enhances Arsenic Trioxide-Induced Apoptosis in NB4 Cells Mol. Pharmacol., July 1, 1999; 56(1): 102 - 109. [Abstract] [Full Text] A. Melnick and J. D. 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Earnshaw Structure and Function in the Nucleus Science, April 24, 1998; 280(5363): 547 - 553. [Abstract] [Full Text] A. Konig, L. Wrazel, R. P. Warrell Jr, R. Rivi, P. P. Pandolfi, A. Jakubowski, and J. L. Gabrilove Comparative Activity of Melarsoprol and Arsenic Trioxide in Chronic B-Cell Leukemia Lines Blood, July 15, 1997; 90(2): 562 - 570. [Abstract] [Full Text] [PDF] E. M. Rego, L.-Z. He, R. P. Warrell Jr., Z.-G. Wang, and P. P. Pandolfi Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RARalpha and PLZF-RARalpha oncoproteins PNAS, August 29, 2000; 97(18): 10173 - 10178. [Abstract] [Full Text] [PDF]

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