ZSTK474, a specific phosphatidylinositol 3-kinase inhibitor, induces G1 arrest of the cell cycle in vivo
ZSTK474, a specific phosphatidylinositol 3-kinase inhibitor, induces G1 arrest of the cell cycle in vivo
复制标题
DOI：
10.1016/j.ejca.2011.10.006
复制
发表时间：
2012-04-01
影响因子：
8.4
通讯作者：
Yamori, Takao
中科院分区：
文献类型：
--
作者：
Dan, Shingo;Okamura, Mutsumi;Yamori, Takao
磷脂酰肌醇3-激酶（PI 3 K）被认为是一个有前途的治疗靶点，因为它经常在癌症中被激活。我们以前报道，ZSTK 474，一个特定的PI 3 K抑制剂，抑制肿瘤细胞增殖，通过G1期阻滞的细胞周期，而不诱导细胞凋亡在体外。然而，尚不清楚ZSTK 474是否诱导G1期阻滞以发挥体内抗肿瘤功效。我们最近开发了一种实时成像系统，名为基于荧光泛素化的细胞周期指示剂（Fucci），以可视化细胞周期分布。在这里，通过使用该系统，我们测试了ZSTK 474是否在体内以及体外诱导肿瘤细胞的G1期阻滞。将Fucci导入的人乳腺癌MCF-7细胞和宫颈癌HeLa细胞皮下异种移植到裸鼠中。将ZSTK 474给予荷瘤小鼠5天，并通过监测活小鼠中的荧光来分析异种移植肿瘤中的细胞周期分布。我们证明，ZSTK 474诱导G1期阻滞沿着体内肿瘤抑制。此外，我们表明，ZSTK 474抑制肿瘤生长，而不诱导细胞凋亡。有趣的是，在ZSTK 474的长期（3个月）给药期间，G1细胞和肿瘤抑制的这种增加得以维持。这些结果表明，ZSTK 474发挥其体内抗肿瘤疗效通过G1期阻滞，但不通过细胞凋亡，只要它是管理，并可用于数月的维持治疗晚期癌症患者。(C)2011爱思唯尔有限公司保留所有权利。
Phosphatidylinositol 3-kinase (PI3K) is regarded as a promising therapeutic target because it is often activated in cancer. We previously reported that ZSTK474, a specific PI3K inhibitor, inhibits tumour cell proliferation via G1 arrest of the cell cycle without inducing apoptosis in vitro. However, it remained unclear whether ZSTK474 induces G1 arrest to exert antitumour efficacy in vivo. We recently developed a live imaging system, named Fluorescent Ubiquitination-based Cell Cycle Indicator (Fucci), to visualise cell cycle distribution. Here, by using this system, we tested whether ZSTK474 induces G1 arrest in tumour cells in vivo, as well as in vitro. Fucci-introduced human breast cancer MCF-7 cells and cervical cancer HeLa cells were subcutaneously xenografted in nude mice. ZSTK474 was administered to the tumour-bearing mice for 5 days, and the cell cycle distribution in the xenografted tumours were analysed by monitoring fluorescence in live mice. We demonstrate that ZSTK474 induces G1arrest along with tumour suppression in vivo. Moreover, we show that ZSTK474 suppresses the tumour growth without inducing apoptosis. Interestingly, such increase in G1 cells and tumour suppression was maintained during long-term (3-month) administration of ZSTK474. These results suggest that ZSTK474 exerts its in vivo antitumour efficacy via G1 arrest but not via apoptosis as long as it is administered, and could be used for months as maintenance therapy for patients with advanced cancers. (C) 2011 Elsevier Ltd. All rights reserved.