Therapeutic targeting of Polo-like kinase-1 and Aurora kinases in T-cell acute lymphoblastic leukemia

被引:29
|
作者
Sparta, Antonino Maria [1 ]
Bressanin, Daniela [1 ]
Chiarini, Francesca [2 ,3 ]
Lonetti, Annalisa [1 ]
Cappellini, Alessandra [4 ]
Evangelisti, Cecilia [1 ]
Evangelisti, Camilla [2 ,3 ]
Melchionda, Fraia [5 ]
Pession, Andrea [5 ]
Bertaina, Alice [6 ]
Locatelli, Franco [6 ]
McCubrey, James A. [7 ]
Martelli, Alberto M. [1 ]
机构
[1] Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy
[2] CNR, Inst Mol Genet, Bologna, Italy
[3] IOR, Muscoloskeletal Cell Biol Lab, Bologna, Italy
[4] Univ Cassino, Dept Human Social & Hlth Sci, I-03043 Cassino, Italy
[5] Univ Bologna, Pediat Oncol & Hematol Unit Lalla Seragnoli, S Orsola Malpighi Hosp, Bologna, Italy
[6] IRCCS Osped Pediat Bambino Gesu, Rome, Italy
[7] E Carolina Univ, Brody Sch Med, Dept Microbiol & Immunol, Greenville, NC USA
关键词
polo-like kinases; Aurora kinases; T-ALL; cell cycle; apoptosis; caspases; PI3K/Akt/mTORC2; MEK/ERK/mTORC1; ACUTE MYELOID-LEUKEMIA; INHIBITOR BI 2536; PLK1; ONCOGENIC TRANSFORMATION; CYTOTOXIC ACTIVITY; MAMMALIAN TARGET; CANCER; PATHWAY; RESISTANCE; RAPAMYCIN;
D O I
10.4161/cc.29267
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Polo-like kinases (PLKs) and Aurora kinases (AKs) act as key cell cycle regulators in healthy human cells. In cancer, these protein kinases are often overexpressed and dysregulated, thus contributing to uncontrolled cell proliferation and growth. T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignancy arising in the thymus from T-cell progenitors. Primary chemoresistant and relapsed T-ALL patients have yet a poor outcome, therefore novel therapies, targeting signaling pathways important for leukemic cell proliferation, are required. Here, we demonstrate the potential therapeutic effects of BI6727, MK-5108, and GSK1070916, three selective inhibitors of PLK1, AK-A, and AK-B/C, respectively, in a panel of T-ALL cell lines and primary cells from T-ALL patients. The drugs were both cytostatic and cytotoxic to T-ALL cells by inducing G(2)/M-phase arrest and apoptosis. The drugs retained part of their pro-apoptotic activity in the presence of MS-5 bone marrow stromal cells. Moreover, we document for the first time that BI6727 perturbed both the PI3K/Akt/mTORC2 and the MEK/ERK/mTORC1 signaling pathways, and that a combination of BI6727 with specific inhibitors of the aforementioned pathways (MK-2206, CCI-779) displayed significantly synergistic cytotoxic effects. Taken together, our findings indicate that PLK1 and AK inhibitors display the potential for being employed in innovative therapeutic strategies for improving T-ALL patient outcome.
引用
收藏
页码:2237 / 2247
页数:11
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