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.
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.
Institute of Nursing and Department of Nursing, Chang Gung University of Science and Technology, Chronic Diseases and Health Promotion Research Center, CGUST, Taiwan.
Chih-Chuan
CC
Teng
Hsing-Chun
HC
Kuo
Ho-Chen
HC
Cheng
Ting-Chung
TC
Wang
Chun-I
CI
Sze
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001254:Astrocytoma / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D004790:Enzyme Induction / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis*; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013778:Tetrazolium Salts; D013844:Thiazoles
C510259:1-(4-(furo(2,3-b)quinolin-4-ylamino)phenyl)ethanone; D000970:Antineoplastic Agents; D011804:Quinolines; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; D020929:Mitogen-Activated Protein Kinase Kinases; C022616:thiazolyl blue