Although recent data shows that
arsenic trioxide (
As2O3) 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 As2O3-mediated cell death are not fully understood. In this study, we investigated the in vitro effects of
As2O3 on cell growth inhibition and cell death in human
T-lymphocytic leukemia and
myelodysplastic syndrome (MDS) cell lines.
As2O3 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
As2O3. Numerous large cytoplasmic inclusions and vacuoles were observed in As2O3-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 microM
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
As2O3 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
As2O3, and provide a suggestion that
As2O3 may be of therapeutic value for the treatment of patients with human
T-lymphocytic leukemia and
myelodysplastic syndrome.