A novel synthetic protoapigenone analogue, WYC02-9, induces DNA damage and apoptosis in DU145 prostate cancer cells through generation of reactive oxygen species

被引:36
作者
Chen, Huei-Mei [1 ,2 ]
Chang, Fang-Rong [1 ,3 ,4 ]
Hsieh, Ya-Ching [2 ]
Cheng, Yu-Jen [5 ]
Hsieh, Kun-Chou [5 ]
Tsai, Lih-Min [2 ]
Lin, An-Shen [1 ]
Wu, Yang-Chang [1 ,6 ,7 ]
Yuan, Shyng-Shiou [2 ,8 ,9 ]
机构
[1] Coll Pharm, Grad Inst Nat Prod, Taipei, Taiwan
[2] E DA Hosp, Dept Med Res, Kaohsiung 824, Taiwan
[3] Kaohsiung Med Univ, Univ Hosp, Ctr Canc, Kaohsiung 807, Taiwan
[4] Natl Sun Yat Sen Univ, Dept Marine Biotechnol & Resources, Kaohsiung 804, Taiwan
[5] I Shou Univ, E DA Hosp, Dept Surg, Div Thorac Surg, Kaohsiung, Kaohsiung Cty, Taiwan
[6] Coll Chinese Med, Grad Inst Integrated Med, Taichung, Taiwan
[7] China Med Univ, Univ Hosp, Nat Med Prod Res Ctr, Taichung 40402, Taiwan
[8] E DA Hosp, Dept Obstet & Gynecol, Kaohsiung 824, Taiwan
[9] I Shou Univ, Dept Biol Sci & Technol, Kaohsiung 824, Taiwan
关键词
WYC02-9; ROS; Prostate cancer; gamma-H2A.X; Delta Psi(m) decrease; Free radicals; MEDIATED APOPTOSIS; PROTEIN-KINASE; ROS; ACTIVATION; MECHANISMS; PATHWAYS; GROWTH; PHOSPHORYLATION; CHEMOPREVENTION; ISOTHIOCYANATE;
D O I
10.1016/j.freeradbiomed.2011.01.015
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
The protoapigenone analogue WYC02-9, a novel synthetic flavonoid, has been shown to act against a variety of experimental tumors. However, its effects on prostate cancer and its mechanism of action are unknown. Thus, WYC02-9 was investigated for its cytotoxicity against DU145 prostate cancer cells, as was the underlying mechanisms by which WYC02-9 might induce DNA damage and apoptotic cell death through reactive oxygen species (ROS). WYC02-9 inhibited the cell growth of three prostate cancer cell lines, especially DU145 cells. In DU145 cells, WYC02-9 increased the generation of intracellular ROS, followed by induction of DNA damage and activation of the ATM-p53-H2A.X pathway and checkpoint-related signals Chk1/Chk2, which led to increased numbers of cells in the S and G2/M phases of the cell cycle. Furthermore, WYC02-9 induced apoptotic cell death through mitochondrial membrane potential decrease and activation of caspase-9, caspase-3, and PARP. The above effects were all prevented by the ROS scavenger N-acetylcysteine. Administration of WYC02-9 in a nude mouse DU145 xenograft model further identified the anti-cancer activity of WYC02-9. These findings therefore suggest that WYC02-9-induced DNA damage and mitochondria-dependent cell apoptosis in DU145 cells are mediated via ROS generation. (C) 2011 Elsevier Inc. All rights reserved.
引用
收藏
页码:1151 / 1162
页数:12
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