Abstract
The purpose of this study was to evaluate the possible involvement of the phosphoinositide 3‐kinase (PI3K)/Akt survival pathway in determining resistance to arsenic trioxide (As~2~O~3~)‐induced apoptosis. We employed a HL60 cell clone (HL60AR) with a constitutively active PI3K/Akt survival pathway, as well as U937 and K562 cells. In addition, we used parental (PT) HL60 cells overexpressing a constitutively active Akt. Selective pharmacological inhibitors of the PI3K/Akt axis (LY294002, wortmannin) were employed to influence the sensitivity to As~2~O~3~. While HL60PT cells were sensitive to 2.5 μM As~2~O~3~ and died of apoptosis, HL60AR cells were resistant up to 5 μM As~2~O~3~. Treatment with either LY294002 or wortmannin lowered resistance of HL60AR cells to As~2~O~3~. Also in U937 and K562 cells, inhibitors of the PI3K/Akt axis caused a decrease in As~2~O~3~ resistance. Overexpression of constitutively active Akt in HL60PT cells caused the induction of resistance to 2.5 μM As~2~O~3~. Conversely, forced expression of a dominant negative Akt in HL60AR cells resulted in a decrease in As~2~O~3~ resistance. Moreover, HL60 cell resistance to 2.5 μM As~2~O~3~ could be significantly reduced by incubation with SN50, a peptide inhibitor selective for the NF‐κB transcription factor. Taken together our findings suggest that a constitutive activation of the PI3K/Akt pathway, which is increasingly detected in some types of acute myeloid leukemia, may contribute to As~2~O~3~ resistance, most likely through NF‐κB activation. Selective pharmacological inhibitors of this survival pathway, as well as of NF‐κB, might be usefully employed in the future to reverse resistance to this treatment. © 2004 Wiley‐Liss, Inc.