Phosphoinositide 3-kinase/Akt inhibition increases arsenic trioxide-induced apoptosis of acute promyelocytic and T-cell leukaemias

Authors: Tabellini, Giovanna¹; Tazzari, Pier Luigi²; Bortul, Roberta³; Evangelisti, Camilla⁴; Billi, Anna Maria⁴; Grafone, Tiziana⁵; Martinelli, Giovanni⁵; Baccarani, Michele⁵; Martelli, Alberto M.

Source: British Journal of Haematology, Volume 130, Number 5, September 2005 , pp. 716-725(10)

Publisher: Blackwell Publishing

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Abstract:

Summary

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 mol/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.

Keywords: apoptosis; leukaemia; protein phoshorylation; signal transduction

Document Type: Research article

DOI: 10.1111/j.1365-2141.2005.05679.x

Affiliations: 1: Dipartimento di Scienze Biomediche e Biotecnologie, Sezione di Citologia e Istologia, Università di Brescia, Brescia 2: Servizio di Immunoematologia e Trasfusionale, Policlinico S.Orsola-Malpighi, Bologna 3: Dipartimento di Morfologia Umana Normale, Università di Trieste, Trieste 4: Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell‘Apparato Locomotore, Sezione di Anatomia, Cell Signalling Laboratory, Università di Bologna, Bologna 5: Istituto di Ematologia ed Oncologia Medica Seràgnoli, Università di Bologna, Bologna

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