The effects of arsenic trioxide (As2O3) on human megakaryocytic leukemia cell lines. With a comparison of its effects on other cell lineages.
Arsenic trioxide (As2O3) has been demonstrated to be effective for the treatment of acute promyelocytic leukemia (APL) and to inhibit proliferation and produce apoptosis in the APL cell line NB4. The effect of this newly utilized chemotherapeutic agent on other lineages is currently under study to evaluate its efficacy for the treatment of other human malignancies and myeloproliferative syndromes. A recent study described the effects of As2O3 upon viability, proliferation, and induction of apoptosis in four different megakaryocytic leukemia cell lines. At pharmacological concentrations (0.5-2 microM) As2O3 selectively inhibits growth and causes apoptosis in the megakaryocytic leukemia cell lines HEL, Meg-01, UT7 and M07e. Pertinently, these concentrations of As2O3 resulted in identical changes in the characteristics of the APL cell line NB4, suggesting that As2O3 could produce its effects in both cellular lineages via a common mechanism of action. Various mechanisms have been proposed for the As2O3-induced changes in NB4 (including modulation of promyelocytic leukemia proteins (PML) and Bcl-2, modification of the glutathione redox system, caspase activation, and cell cycle arrest) and are currently under investigation in the megakaryocytic leukemia cell lines. Recent preliminary results indicate that As2O3 downregulates Bcl-2 expression and induces cell cycle arrest in megakaryocytic cell lines. The use of As2O3 for the treatment of malignant megakaryocytic disorders also has been considered. The in vitro effects of As2O3 on a chronic megakaryocytic proliferative disorder. i.e., Essential Thrombocythemia (ET), have been analyzed and megakaryocyte progenitors have shown an unexpectedly higher resistance to As2O3, in comparison to normal megakaryocyte colony-forming cells. The effects of As2O3 on ET and other megakaryocytic disorders need to be fully examined, in order to determine the clinical efficacy of As2O3 in the treatment of syndromes affecting the megakaryocytic lineage.
Alemany
M
M
Institut des Vaisseaux et du Sang, Hôpital Lariboisière, Paris, France. mon_alem@club-internet.fr
Levin
J
J
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use*; D019070:Cell Lineage / Q000187:drug effects*; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000188:drug therapy* / Q000473:pathology*; D008533:Megakaryocytes / Q000187:drug effects* / Q000473:pathology*; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use*; D013922:Thrombocytosis / Q000188:drug therapy / Q000473:pathology
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D000077237:Arsenic Trioxide