Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via up-regulation of Beclin-1

Although recent data shows that arsenic trioxide (AS(2)O(3)) is capable of inducing cell death via cell cycle arrest and apoptosis both in acute promyelocytic leukemia (APL) and in non-APL cells, the mechanisms of AS(2)O(3)-mediated cell death are not fully understood. In this study, we investigated the in vitro effects of AS(2)O(3) on cell growth inhibition and cell death in human T-lymphocytic leukemia and myelodysplastic syndrome (MDS) cell lines. AS(2)O(3) significantly inhibited the proliferation of Molt-4 and Mutz-1 cells in dose- and time-dependent manner. Autophagic cell death (programmed cell death type II) and apoptosis (programmed cell death type I) were activated together in leukemia cell lines after exposed to AS(2)O(3). Numerous large cytoplasmic inclusions and vacuoles were observed in AS(2)O(3)-treated cells using electron microscope. Furthermore, 3-methyladenine (an autophagy inhibitor) significantly reduced autophagic cell death and sequentially induced apoptosis. Finally, leukemia cells treated with 4 mu M As2O3 showed a considerable up-regulation of Beclin-1 (a Bcl-2-interacting protein) expression, which was independent of transcription of mRNA and required protein synthesis. In addition, Molt-4 cells treated with AS(2)O(3) exhibited the down-regulation of Bax protein expression, suggesting that Bax may be involved in accumulating of Beclin-1 and triggering autophagic cell death in As2O3-treated leukemia cells. These results may lead to a better understanding of the mechanism of action of AS(2)O(3), and provide a suggestion that AS(2)O(3) may be of therapeutic value for the treatment of patients with human T-lyrnphocytic leukemia and myelodysplastic syndrome. (c) 2006 Elsevier Ltd. All rights reserved.