University of Rostock, Division of Medicine, Department of Hematology, Oncology and Palliative Medicine, Ernst Heydemann Str. 6, 18057 Rostock, Germany.
Anticancer Res. 2012 Feb;32(2):463-74.
Inhibition of signal transduction pathways has been successfully introduced into cancer treatment. The dual phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 has antitumor activity in vitro against solid tumors. Here, we examined the activity of NVP-BEZ235 in acute lymphoblastic leukemia (ALL) cells and the best modalities for combination approaches.
ALL cell lines (SEM, RS4;11, Jurkat and MOLT4) were treated with NVP-BEZ235 alone, or in combination with cytarabine (AraC), doxorubicin (Doxo) or dexamethasone (Dexa).
NVP-BEZ235 potently inhibited the proliferation and metabolic activity of ALL cells. Antiproliferative effects were associated with G(0)/G(1) arrest and reduced levels of cyclin-dependent kinase 4 (CDK4) and cyclin D3. Inhibition of PI3K and mTOR activity was detected at 10 and 100 nM. NVP-BEZ235 combined with AraC, Doxo or Dexa synergistically enhanced the cytotoxicity compared to single-drug treatment, even in glucocorticoid-resistant cells.
NVP-BEZ235 displays pronounced antiproliferative effects in ALL cells and might therefore be a useful drug in the treatment of ALL.
信号转导通路的抑制已成功应用于癌症治疗。双重磷脂酰肌醇 3-激酶（PI3K）和哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂 NVP-BEZ235 在体外对实体瘤具有抗肿瘤活性。在这里，我们研究了 NVP-BEZ235 在急性淋巴细胞白血病（ALL）细胞中的活性以及联合治疗的最佳方式。
用 NVP-BEZ235 单独或与阿糖胞苷（AraC）、多柔比星（Doxo）或地塞米松（Dexa）联合处理 ALL 细胞系（SEM、RS4;11、Jurkat 和 MOLT4）。
NVP-BEZ235 强烈抑制 ALL 细胞的增殖和代谢活性。抗增殖作用与 G(0)/G(1)期阻滞和细胞周期蛋白依赖性激酶 4（CDK4）和细胞周期蛋白 D3 水平降低有关。在 10 和 100 nM 时检测到 PI3K 和 mTOR 活性的抑制。与单药治疗相比，NVP-BEZ235 与 AraC、Doxo 或 Dexa 联合使用可协同增强细胞毒性，即使在糖皮质激素耐药细胞中也是如此。
NVP-BEZ235 在 ALL 细胞中显示出明显的增殖抑制作用，因此可能是 ALL 治疗的有用药物。
