Preclinical testing of the Akt inhibitor triciribine in T-cell acute lymphoblastic leukemia.
Over the past 20 years, survival rates of T-cell acute lymphoblastic leukemia (T-ALL) patients have improved, mainly because of advances in polychemotherapy protocols. Despite these improvements, we still need novel and less toxic treatment strategies targeting aberrantly activated signaling networks which increase proliferation, survival, and drug resistance of T-ALL cells. One such network is represented by the phosphatidylinositol 3-kinase (PI3K)/Akt axis. PI3K inhibitors have displayed some promising effects in preclinical models of T-ALL. Here, we have analyzed the therapeutic potential of the Akt inhibitor, triciribine, in T-ALL cell lines. Triciribine caused cell cycle arrest and caspase-dependent apoptosis. Western blots demonstrated a dose-dependent dephosphorylation of Akt1/Akt2, and of mammalian target of rapamycin complex 1 downstream targets in response to triciribine. Triciribine induced autophagy, which could be interpreted as a defensive mechanism, because an autophagy inhibitor (chloroquine) increased triciribine-induced apoptosis. Triciribine synergized with vincristine, a chemotherapeutic drug employed for treating T-ALL patients, and targeted the side population of T-ALL cell lines, which might correspond to leukemia initiating cells. Our findings indicate that Akt inhibition, either alone or in combination with chemotherapeutic drugs, may serve as an efficient treatment towards T-ALL cells requiring upregulation of this signaling pathway for their proliferation and survival.
Evangelisti
Camilla
C
Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Cell Signalling Laboratory, Università di Bologna, Bologna, Italy.
Ricci
Francesca
F
Tazzari
Pierluigi
P
Chiarini
Francesca
F
Battistelli
Michela
M
Falcieri
Elisabetta
E
Ognibene
Andrea
A
Pagliaro
Pasqualepaolo
P
Cocco
Lucio
L
McCubrey
James A
JA
Martelli
Alberto M
AM
D001343:Autophagy / Q000187:drug effects; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046529:Microscopy, Electron, Transmission; D046912:Multiprotein Complexes; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000473:pathology; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology*; D058985:Side-Population Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology
C493245:CRTC2 protein, human; D046912:Multiprotein Complexes; D011506:Proteins; D012263:Ribonucleosides; D014157:Transcription Factors; C023764:triciribine; D014750:Vincristine; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D053453:Caspase 9