Phosphoinositide 3-kinase/Akt inhibition increases arsenic trioxide-induced apoptosis of acute promyelocytic and T-cell leukaemias.
Recent studies suggest that the prosurvival signal transduction pathway involving phosphoinositide 3-kinase (PI3K)/Akt can confer an aggressive, apoptosis-resistant phenotype to acute leukaemia cells. We have investigated the effect of modulating this signalling pathway on the sensitivity of leukaemic cell lines (NB-4, CEM, Jurkat, MOLT-4) and acute promyelocytic primary blasts to apoptosis induced by 1 micromol/l As2O3. Whereas parental NB-4 cells did not display any phosphorylated (active) Akt, CEM, Jurkat and MOLT-4 cells exhibited high levels of Akt activation. Consistently, treatment of NB-4 cells with pharmacological inhibitors of the PI3K/Akt pathway (LY294002, wortmannin) did not increase sensitivity of these cells to arsenic trioxide (As2O3), whereas siRNA knock-down of Akt enhanced As2O3-induced apoptosis of CEM, Jurkat and MOLT-4 cells. Overexpression of a constitutively active Akt cDNA rendered NB-4 cells less susceptible to As2O3. Upon prolonged exposure to As2O3, we isolated a NB-4 cell clone that was resistant to As2O3 and displayed high levels of active Akt. LY294002 treatment of acute promyelocytic primary blasts with elevated Akt phosphorylation levels resulted in an increased sensitivity to As2O3. These results may provide a rationale for the development of combined or sequential treatment with PI3K/Akt inhibitors to improve the efficacy of As2O3 on acute leukaemias and also to overcome As2O3 resistance.
Tabellini
Giovanna
G
Dipartimento di Scienze Biomediche e Biotecnologie, Sezione di Citologia e Istologia, Università di Brescia, Brescia, Italy.
Tazzari
Pier Luigi
PL
Bortul
Roberta
R
Evangelisti
Camilla
C
Billi
Anna Maria
AM
Grafone
Tiziana
T
Martinelli
Giovanni
G
Baccarani
Michele
M
Martelli
Alberto M
AM
D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D019169:Jurkat Cells; D007938:Leukemia / Q000473:pathology*; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D015458:Leukemia, T-Cell / Q000473:pathology; D010087:Oxides / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured
D001152:Arsenicals; D010087:Oxides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D000077237:Arsenic Trioxide