Antitumor activity of AZ64 via G2/M arrest in non-small cell lung cancer
Antitumor activity of AZ64 via G2/M arrest in non-small cell lung cancer
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DOI：
10.3892/ijo.2012.1619
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发表时间：
2012-11-01
影响因子：
5.2
通讯作者：
Mao, Li
中科院分区：
文献类型：
--
作者：
Xue, Yuwen;Ren, Hening;Mao, Li
AZ64 是一种新型抗肿瘤药物，设计为原肌球蛋白相关激酶 (Trk) 抑制剂；然而，其对肺癌的作用及其作用机制仍不清楚。本研究旨在阐明AZ64的抗肿瘤活性及其对抗非小细胞肺癌（NSCLC）的作用机制。我们的结果表明，AZ64 对 NSCLC 细胞具有有效的抗增殖作用，并且以剂量和时间依赖性方式发挥作用。我们还证明 AZ64 抑制 NSCLC 细胞的贴壁依赖性生长和侵袭。体内实验表明，AZ64显着降低裸鼠NSCLC异种移植瘤的生长，且耐受性良好。机制实验表明，AZ64 通过在 G2/M 转变时磷酸化 Cdc2 (Tyr15) 的积累，继 Cdc25C 表达下调后，诱导 NSCLC 细胞的 G2/M 阻滞。总的来说，我们的数据表明，AZ64 是一种潜在的抗肿瘤药物，可用于治疗 NSCLC，其通过抑制磷酸 Cdc2 (Tyr15) 的去磷酸化来靶向 G2/M 转变而发挥作用。
AZ64 is a novel antitumor agent designed as a tropomyosin-related kinase (Trk) inhibitor; however, its effect on lung cancer and its mechanism of action remain unclear. This study aimed to elucidate the antitumor activity of AZ64 and its mechanism of action against non-small cell lung cancer (NSCLC). Our results demonstrate that AZ64 has a potent anti-proliferative effect on NSCLC cells and acts in a dose- and time-dependent manner. We also demonstrate that AZ64 suppresses the anchorage-independent growth and invasion of NSCLC cells. In vivo experiments demonstrated that AZ64 significantly reduced the tumor growth of NSCLC xenografts in nude mice and was well-tolerated. Mechanistic experiments revealed that AZ64 induced the G2/M arrest of NSCLC cells by the accumulation of phospho-Cdc2 (Tyr15) at the G2/M transition, following the downregulation of Cdc25C expression. Collectively, our data demonstrate that AZ64 is a potential antitumor drug that may be used for the treatment of NSCLC, which functions by targeting the G2/M transition via the inhibition of the dephosphorylation of phospho-Cdc2 (Tyr15).