Department of Human Anatomy, University of Bologna, Bologna, Italy.
Cancer Res. 2010 Oct 15;70(20):8097-107. doi: 10.1158/0008-5472.CAN-10-1814. Epub 2010 Sep 28.
Recent findings have highlighted that constitutively active phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) 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/Akt/mTOR inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the novel dual PI3K/mTOR inhibitor NVP-BEZ235, an orally bioavailable imidazoquinoline derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. NVP-BEZ235 was cytotoxic to a panel of T-ALL cell lines as determined by MTT assays. NVP-BEZ235 treatment resulted in cell cycle arrest and apoptosis. Western blots showed a dose- and time-dependent dephosphorylation of Akt and mTORC1 downstream targets in response to NVP-BEZ235. Remarkably, NVP-BEZ235 targeted the side population of both T-ALL cell lines and patient lymphoblasts, which might correspond to leukemia-initiating cells, and synergized with chemotherapeutic agents (cyclophosphamide, cytarabine, dexamethasone) currently used for treating T-ALL patients. NVP-BEZ235 reduced chemoresistance to vincristine induced in Jurkat cells by coculturing with MS-5 stromal cells, which mimic the bone marrow microenvironment. NVP-BEZ235 was cytotoxic to T-ALL patient lymphoblasts displaying pathway activation, where the drug dephosphorylated eukaryotic initiation factor 4E-binding protein 1, at variance with rapamycin. Taken together, our findings indicate that longitudinal inhibition at two nodes of the PI3K/Akt/mTOR network with NVP-BEZ235, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment of those T-ALLs that have aberrant upregulation of this signaling pathway for their proliferation and survival.
最近的研究结果表明，持续激活的磷脂酰肌醇 3-激酶（PI3K）/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路是 T 细胞急性淋巴细胞白血病（T-ALL）的共同特征，它上调细胞增殖、存活和耐药性。这些观察结果有力地支持了在 T-ALL 治疗中应用 PI3K/Akt/mTOR 抑制剂。在这里，我们分析了新型双重 PI3K/mTOR 抑制剂 NVP-BEZ235 的治疗潜力，NVP-BEZ235 是一种可口服的咪唑并喹啉衍生物，已进入实体瘤的临床试验。MTT 测定法确定 NVP-BEZ235 对一系列 T-ALL 细胞系均具有细胞毒性。NVP-BEZ235 处理导致细胞周期停滞和细胞凋亡。Western blot 显示 NVP-BEZ235 剂量依赖性和时间依赖性地下调 Akt 和 mTORC1 下游靶标。值得注意的是，NVP-BEZ235 靶向 T-ALL 细胞系和患者淋巴母细胞的侧群，这可能对应于白血病起始细胞，并且与目前用于治疗 T-ALL 患者的化疗药物（环磷酰胺、阿糖胞苷、地塞米松）协同作用。NVP-BEZ235 降低了 Jurkat 细胞与模拟骨髓微环境的 MS-5 基质细胞共培养时对长春新碱诱导的耐药性。NVP-BEZ235 对显示通路激活的 T-ALL 患者淋巴母细胞具有细胞毒性，药物使真核起始因子 4E 结合蛋白 1 去磷酸化，与雷帕霉素不同。总之，我们的研究结果表明，用 NVP-BEZ235 纵向抑制 PI3K/Akt/mTOR 网络的两个节点，无论是单独使用还是与化疗药物联合使用，都可能是治疗那些由于该信号通路异常上调而增殖和存活的 T-ALL 的有效方法。
