Phosphoinositide 3-kinase/Akt involvement in arsenic trioxide resistance of human leukemia cells.
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 microM As2O3 and died of apoptosis, HL60AR cells were resistant up to 5 microM 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 microM 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 microM As2O3 could be significantly reduced by incubation with SN50, a peptide inhibitor selective for the NF-kappaB 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-kappaB activation. Selective pharmacological inhibitors of this survival pathway, as well as of NF-kappaB, might be usefully employed in the future to reverse resistance to this treatment.
Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Sezione di Anatomia, Cell Signalling Laboratory, Università di Bologna, Italy.
Giovanna
G
Tabellini
Alessandra
A
Cappellini
Pier Luigi
PL
Tazzari
Federica
F
Falà
Anna Maria
AM
Billi
Lucia
L
Manzoli
Lucio
L
Cocco
Alberto M
AM
Martelli
D000730:Androstadienes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004351:Drug Resistance; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000503:physiopathology*; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D052002:NF-kappa B p50 Subunit; D010087:Oxides / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase; D010455:Peptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D000970:Antineoplastic Agents; D000077237:Arsenic Trioxide; D001152:Arsenicals; D020169:Caspases; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D010087:Oxides; D051059:PTEN Phosphohydrolase; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins; D000077191:Wortmannin; C118258:SN50 peptide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human; C494929:PTEN protein, human