Institute of Nursing and Department of Nursing, Chang Gung University of Science and Technology, Chronic Diseases and Health Promotion Research Center, CGUST, Taiwan.
Toxicol Appl Pharmacol. 2012 Aug 15;263(1):73-80. doi: 10.1016/j.taap.2012.05.025. Epub 2012 Jun 7.
CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone) is the major active agent of the alkaloid derivative of Camptotheca acuminata, with multiple pharmacological activities, including anticancer effects and promotion of apoptosis. The mechanism by which CIL-102 inhibits growth remains poorly understood in human astrocytoma cells. Herein, we investigated the molecular mechanisms by which CIL-102 affects the generation of reactive oxygen species (ROS) and cell cycle G2/M arrest in glioma cells. Treatment of U87 cells with 1.0μM CIL-102 resulted in phosphorylation of extracellular signal-related kinase (ERK1/2), downregulation of cell cycle-related proteins (cyclin A, cyclin B, cyclin D1, and cdk1), and phosphorylation of cdk1Tyr(15) and Cdc25cSer(216). Furthermore, treatment with the ERK1/2 inhibitor PD98059 abolished CIL-102-induced Cdc25cSer(216) expression and reversed CIL-102-inhibited cdk1 activation. In addition, N-acetyl cysteine (NAC), an ROS scavenger, blocked cell cycle G2/M arrest and phosphorylation of ERK1/2 and Cdc25cSer(216) in U87 cells. CIL-102-mediated ERK1/2 and ROS production, and cell cycle arrest were blocked by treatment with specific inhibitors. In conclusion, we have identified a novel CIL-102-inhibited proliferation in U87 cells by activating the ERK1/2 and Cdc25cSer(216) cell cycle-related proteins and inducing ROS production; this might be a new mechanism in human astrocytoma cells.
CIL-102（1-[4-（呋喃[2,3-b]喹啉-4-基氨基）苯基]乙酮）是喜树碱衍生物的主要活性成分，具有多种药理活性，包括抗癌作用和促进细胞凋亡。CIL-102 抑制人星形细胞瘤生长的机制尚不清楚。在此，我们研究了 CIL-102 影响活性氧（ROS）产生和细胞周期 G2/M 期阻滞的分子机制。用 1.0μM CIL-102 处理 U87 细胞可导致细胞外信号相关激酶（ERK1/2）磷酸化，细胞周期相关蛋白（cyclin A、cyclin B、cyclin D1 和 cdk1）下调，以及 cdk1Tyr（15）和 Cdc25cSer（216）磷酸化。此外，用 ERK1/2 抑制剂 PD98059 处理可消除 CIL-102 诱导的 Cdc25cSer（216）表达，并逆转 CIL-102 抑制的 cdk1 激活。此外，ROS 清除剂 N-乙酰半胱氨酸（NAC）阻断 U87 细胞的细胞周期 G2/M 期阻滞和 ERK1/2 和 Cdc25cSer（216）的磷酸化。CIL-102 介导的 ERK1/2 和 ROS 产生以及细胞周期阻滞被特异性抑制剂处理所阻断。总之，我们已经确定了 CIL-102 通过激活 ERK1/2 和 Cdc25cSer（216）细胞周期相关蛋白和诱导 ROS 产生来抑制 U87 细胞增殖的新机制；这可能是人类星形细胞瘤细胞的一个新机制。
