Autophagy is a critical mechanism for the induction of the antileukemic effects of arsenic trioxide

Arsenic trioxide (As₂O₃) exhibits potent antitumor effects in vitro and in vivo, but the precise mechanisms by which it generates such responses are not well understood. We provide evidence that As ₂O₃ is a potent inducer of autophagy in leukemia cells. Such induction of autophagy by As₂O₃ appears to require activation of the MEK/ERK pathway but not the AKT/mammalian target of rapamycin or JNK pathways. In efforts to understand the functional relevance of arsenic-induced autophagy, we found that pharmacological inhibitors of autophagy or molecular targeting of beclin 1 or Atg7 results in reversal of the suppressive effects of As₂O₃ on leukemic cell lines and primary leukemic progenitors from acute myelogenous leukemia patients. Altogether, our data provide direct evidence that autophagic cell death is critical for the generation of the effects of As₂O₃ on acute myelogenous leukemia cells and raise the potential of modulation of elements of the autophagic machinery as an approach to enhance the antitumor properties of As₂O₃ and possibly other heavy metal derivatives.