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Updated: Jun 8, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Preclinical testing of the Akt inhibitor triciribine in T-cell acute lymphoblastic leukemia
Camilla Evangelisti1, Francesca Ricci, Pierluigi Tazzari
1Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Cell Signalling Laboratory, Università di Bologna, Bologna, Italy.
Abstract:
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.
Insights
The Akt inhibitor triciribine shows promise for treating T-cell acute lymphoblastic leukemia (T-ALL). It induces cancer cell death and enhances chemotherapy effectiveness, offering a potential new strategy for T-ALL treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- T-cell acute lymphoblastic leukemia (T-ALL) survival rates have improved due to chemotherapy.
- Novel, less toxic treatments are needed to overcome drug resistance and target key signaling pathways in T-ALL.
- The phosphatidylinositol 3-kinase (PI3K)/Akt signaling axis is implicated in T-ALL proliferation, survival, and drug resistance.
Purpose of the Study:
- To investigate the therapeutic potential of the Akt inhibitor triciribine in T-ALL cell lines.
- To understand the mechanisms of triciribine's action, including its effects on cell cycle, apoptosis, and signaling pathways.
- To evaluate triciribine's efficacy alone and in combination with existing T-ALL therapies.
Main Methods:
- T-cell acute lymphoblastic leukemia cell lines were treated with triciribine.
- Cell cycle arrest and apoptosis were assessed using relevant assays.
- Western blotting was used to analyze the phosphorylation status of Akt and downstream targets.
- Autophagy was evaluated, and its role was studied using an autophagy inhibitor (chloroquine).
- Synergistic effects of triciribine with vincristine were investigated.
Main Results:
- Triciribine induced cell cycle arrest and caspase-dependent apoptosis in T-ALL cells.
- Triciribine treatment led to dose-dependent dephosphorylation of Akt1/Akt2 and mTORC1 targets.
- Triciribine induced autophagy, and inhibiting autophagy enhanced triciribine-induced apoptosis.
- Triciribine demonstrated synergistic effects with vincristine and targeted the side population of T-ALL cells.
Conclusions:
- Akt inhibition by triciribine is a promising therapeutic strategy for T-ALL.
- Triciribine induces T-ALL cell death and may overcome drug resistance.
- Combining Akt inhibitors with chemotherapy could be an effective treatment approach for T-ALL.
