Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells.
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.
Chen
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GQ
Shanghai Institute of Hematology, Samuel Waxman Cancer Research Foundation Lab, Rui-Jin Hospital, China.
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Tang
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Xiong
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Zhu
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Cai
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Han
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Shi
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Jia
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Liu
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Niu
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Zhang
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Paul
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Naoe
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Kitamura
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Miller
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Waxman
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Wang
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Chen
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D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D020261:Arsenic Poisoning; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016130:Immunophenotyping; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D010087:Oxides / Q000627:therapeutic use / Q000633:toxicity*; D010587:Phagocytosis / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000032:analysis / Q000096:biosynthesis; D000072482:Retinoic Acid Receptor alpha; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D014212:Tretinoin / Q000633:toxicity; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001152:Arsenicals; D004273:DNA, Neoplasm; D010087:Oxides; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D000077237:Arsenic Trioxide