The role and mechanism of AZD5363 anti-leukemia activity in T-cell acute lymphoblastic leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and heterogeneous hematologic malignancy. Chemotherapy resistance and refractory relapses are the most important challenges in T-ALL. PI3K/Akt/mTOR pathway has been implicated in regulating cell survival, T-ALL development and resistance to chemotherapy. We explored the effects of AZD5363 (a potent pan-Akt inhibitor) alone and in combination with autophagy inhibitor hydroxycholoroquine sulfate (HCQ) in cultured CCRF-CEM, Jurkat and PF382 cells and a T-ALL xenograft mouse model. METHODS: A xenograft mouse model was used to investigate the effect of AZD5363 on T-ALL progression. MTT assay, flow cytometry, siRNA, transmission electron microscopy and western blotting were performed in cultured CCRF-CEM, Jurkat and PF382 cells. The interaction between AZD5363 and HCQ was explored by molecular docking. RESULTS: AZD5363 delayed T-ALL progression and increased the expression of cleaved caspase-3 and LC3B-II in mice. AZD5363 decreased cells viability by arresting cell cycle in the G1 phase and inducing apoptosis, and, significantly increased the number of autophagosomes (p < 0.01). The increased expression of cleaved caspase-3 and LC3B-II, and phosphorylation of Akt and mTOR were significantly, inhibited by AZD5363. HCQ blocked AZD5363-induced autophagy and enhanced AZD5363-induced cell death (p < 0.01). CONCLUSIONS: AZD5363 suppressed T-ALL progression and its anti-leukemia activity was enhanced by HCQ in T-ALL cells, which might provide a potential therapeutic strategy for human T-ALL.

[PI3K/AKT/mTOR Pathway and Pediatric T Acute Lymphoblastic Leukemia-Review].

The PI3K/Akt/mTOR signaling pathway plays a central role in cell growth, proliferation and survival in physiological conditions. This signal pathway is considered to be an innovative targeted therapy of cancer, and its abnormal activation has been proved to be related to T-cell acute lymphoblastic leukemia (T-ALL) .Despite improved treatment strategies, such as multi-drug combination, high-dose chemotherapy and all kinds of application and popularization of hematopoietic stem cell transplantation, children with drug resistance or relapse T-ALL are still rather worse and its overall outcome and prognosis are much poorer than the more common B-lineage ALL. Therefore, more effective and less cytotoxic treatment targeted strategies for leukemia greatly needed. This review focuses on the relationship between the PI3k/Akt/mTOR pathway and the pediatric T-ALL, so as to reveal the exact molecular mechanism of T-ALL and provide more directions for its treatment.