期刊
LEUKEMIA
卷 28, 期 6, 页码 1196-1206出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2013.369
关键词
T-cell acute lymphoblastic leukemia; PI3K; apoptosis; cell cycle; targeted therapy; chemotherapy
资金
- MIUR FIRB [RBAP10447J_003]
- Fundacao para a Ciencia e a Tecnologia (FCT), Portugal [PTDC/SAU-OBD/104816/2008, PTDC/SAU-ONC/122428/2010]
- FCT [SFRH/BPD/63920/2009]
- Special Project AIRC 5x1000 [9962]
- Progetto di rilevante Interesse Nazionale, PRIN
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-OBD/104816/2008, SFRH/BPD/63920/2009, PTDC/SAU-ONC/122428/2010] Funding Source: FCT
Constitutively active phosphoinositide 3-kinase (PI3K) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival and drug resistance. These observations lend compelling weight to the application of PI3K inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the pan-PI3K inhibitor NVP-BKM120 (BKM120), an orally bioavailable 2,6-dimorpholino pyrimidine derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. BKM120 treatment resulted in G(2)/M phase cell cycle arrest and apoptosis, being cytotoxic to a panel of T-ALL cell lines and patient T lymphoblasts, and promoting a dose-and time-dependent dephosphorylation of Akt and S6RP. BKM120 maintained its pro-apoptotic activity against Jurkat cells even when cocultured with MS-5 stromal cells, which mimic the bone marrow microenvironment. Remarkably, BKM120 synergized with chemotherapeutic agents currently used for treating T-ALL patients. Moreover, in vivo administration of BKM120 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth, thus prolonging survival time. Taken together, our findings indicate that BKM120, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment for T-ALLs that have aberrant upregulation of the PI3K signaling pathway.
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