Giovanna Tabellini and Alessandra Cappellini equally contributed to this work.
Phosphoinositide 3-kinase/Akt involvement in arsenic trioxide resistance of human leukemia cells†
Article first published online: 12 AUG 2004
Copyright © 2004 Wiley-Liss, Inc.
Journal of Cellular Physiology
Volume 202, Issue 2, pages 623–634, February 2005
How to Cite
Tabellini, G., Cappellini, A., Tazzari, P. L., Falà, F., Billi, A. M., Manzoli, L., Cocco, L. and Martelli, A. M. (2005), Phosphoinositide 3-kinase/Akt involvement in arsenic trioxide resistance of human leukemia cells. J. Cell. Physiol., 202: 623–634. doi: 10.1002/jcp.20153
- Issue published online: 23 NOV 2004
- Article first published online: 12 AUG 2004
- Manuscript Accepted: 26 MAY 2004
- Manuscript Received: 27 JAN 2004
- Italian MIUR Cofin 2002 and 2003
- Italian MIUR FIRB 2001
- Selected Topics Research Fund from Bologna University
- CARISBO Foundation
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 (As2O3)-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 As2O3. While HL60PT cells were sensitive to 2.5 μM As2O3 and died of apoptosis, HL60AR cells were resistant up to 5 μM As2O3. Treatment with either LY294002 or wortmannin lowered resistance of HL60AR cells to As2O3. Also in U937 and K562 cells, inhibitors of the PI3K/Akt axis caused a decrease in As2O3 resistance. Overexpression of constitutively active Akt in HL60PT cells caused the induction of resistance to 2.5 μM As2O3. Conversely, forced expression of a dominant negative Akt in HL60AR cells resulted in a decrease in As2O3 resistance. Moreover, HL60 cell resistance to 2.5 μM As2O3 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 As2O3 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.