The inhibitory effect of CIL-102 on the growth of human astrocytoma cells is mediated by the generation of reactive oxygen species and induction of ERK1/2 MAPK.

Abstract

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.

• Authors: Chih-Chuan Teng, Hsing-Chun Kuo, Ho-Chen Cheng, Ting-Chung Wang, Chun-I Sze
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 263 Issue 1 Pg. 73-80 (Aug 15 2012) ISSN: 1096-0333 [Electronic] United States
• PMID: 22683510 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• 1-(4-(furo(2,3-b)quinolin-4-ylamino)phenyl)ethanone
• Antineoplastic Agents
• Quinolines
• Reactive Oxygen Species
• Tetrazolium Salts
• Thiazoles
• Mitogen-Activated Protein Kinase Kinases
• thiazolyl blue

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Astrocytoma (drug therapy)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Central Nervous System Neoplasms (drug therapy)
• Enzyme Induction (drug effects)
• Glioblastoma (drug therapy)
• Humans
• Mitogen-Activated Protein Kinase Kinases (biosynthesis)
• Quinolines (pharmacology, therapeutic use)
• Reactive Oxygen Species (metabolism)
• Tetrazolium Salts
• Thiazoles