Effects of NVP-BEZ235, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines
Effects of NVP-BEZ235, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines
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DOI：
10.3892/ol.2018.7979
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发表时间：
2018-04-01
期刊：
影响因子：
2.9
通讯作者：
Mori, Naoki
中科院分区：
文献类型：
--
作者：
Ishikawa, Chie;Senba, Masachika;Mori, Naoki
成人 T 细胞白血病 (ATL) 是一种由人类 T 细胞白血病病毒 1 型 (HTLV-1) 引起的侵袭性恶性肿瘤。在 ATL 中，磷脂酰肌醇 3-激酶 (PI3K)/Akt/哺乳动物雷帕霉素靶标 (mTOR) 信号通路持续活跃，促进细胞增殖、存活和化疗耐药。因此，PI3K信号通路是ATL有吸引力的治疗靶点。在本研究中，比较了 RAD001（一种 mTOR 抑制剂）、NVP-BKM120（一种泛 PI3K 抑制剂）和 NVP-BEZ235（一种新型双 PI3K/mTOR 抑制剂）对培养的 HTLV-1 感染的 T 细胞系的影响。结果表明，与 RAD001 和 NVP-BKM120 相比，NVP-BEZ235 在抑制细胞生长方面更有效。 NVP-BEZ235 对各种 HTLV-1 感染的 T 细胞系表现出细胞抑制作用，而非细胞毒性作用，诱导细胞周期停滞在 G(1) 期。 NVP-BEZ235 下调细胞周期蛋白 D1、细胞周期蛋白 D2、细胞周期蛋白 E、细胞周期蛋白依赖性激酶 (CDK)2 和 CDK4 的表达以及视网膜母细胞瘤蛋白的磷酸化。在植入 HTLV-1 感染的 HUT-102 细胞的 C.B-17/Icr 严重联合免疫缺陷小鼠中，与对照组相比，口服 NVP-BEZ235 导致肿瘤生长明显延迟。目前的体外和体内研究强调了 NVP-BEZ235 治疗后对 PI3K 和 mTOR 的有效双重抑制。因此，本研究的结果为 I 期临床研究提供了临床前理论依据，以检查 NVP-BEZ235 对 ATL 患者的影响。
Adult T-cell leukemia (ATL) is an aggressive type of malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). In ATL, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is constitutively active, promoting cell proliferation, survival and chemoresistance. Thus, the PI3K signaling pathway is an attractive therapeutic target for ATL. In the present study, the effects of RAD001 (an mTOR inhibitor), NVP-BKM120 (a pan-PI3K inhibitor) and NVP-BEZ235 (a novel dual PI3K/mTOR inhibitor) on cultured HTLV-1-infected T-cell lines were compared. The results demonstrated that NVP-BEZ235 was more efficacious compared with RAD001 and NVP-BKM120 at inhibiting cell growth. NVP-BEZ235 exhibited cytostatic rather than cytotoxic effects on various HTLV-1-infected T-cell lines, where it induced cell cycle arrest at G(1) phase. NVP-BEZ235 downregulated cyclin D1, cyclin D2, cyclin E, cyclin dependent kinase (CDK)2 and CDK4 expression, and the phosphorylation of retinoblastoma protein. In C.B-17/Icr-severe combined immune deficiency mice implanted with HTLV-1-infected HUT-102 cells, oral NVP-BEZ235 caused marked retardation of tumor growth compared with the control. The present in vitro and in vivo studies highlight the efficacious dual inhibition of PI3K, and mTOR following NVP-BEZ235 treatment. Thus, the results of the current study provide preclinical rationale for phase I clinical studies to examine the effects of NVP-BEZ235 in patients with ATL.