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Phosphoinositide 3‐kinase/Akt inhibition increases arsenic trioxide‐induced apoptosis of acute promyelocytic and T‐cell leukaemias
Author(s) -
Tabellini Giovanna,
Tazzari Pier Luigi,
Bortul Roberta,
Evangelisti Camilla,
Billi Anna Maria,
Grafone Tiziana,
Martinelli Giovanni,
Baccarani Michele,
Martelli Alberto M.
Publication year - 2005
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2005.05679.x
Subject(s) - protein kinase b , arsenic trioxide , jurkat cells , pi3k/akt/mtor pathway , ly294002 , acute promyelocytic leukemia , cancer research , wortmannin , apoptosis , biology , phosphorylation , microbiology and biotechnology , cell culture , signal transduction , chemistry , immunology , biochemistry , t cell , retinoic acid , immune system , genetics
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 μ mol/l As 2 O 3 . 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 (As 2 O 3 ), whereas siRNA knock‐down of Akt enhanced As 2 O 3 ‐induced apoptosis of CEM, Jurkat and MOLT‐4 cells. Overexpression of a constitutively active Akt cDNA rendered NB‐4 cells less susceptible to As 2 O 3 . Upon prolonged exposure to As 2 O 3 , we isolated a NB‐4 cell clone that was resistant to As 2 O 3 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 As 2 O 3 . These results may provide a rationale for the development of combined or sequential treatment with PI3K/Akt inhibitors to improve the efficacy of As 2 O 3 on acute leukaemias and also to overcome As 2 O 3 resistance.