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

作者：Chen, Huei Mei; Chang, Fang Rong; Hsieh, Ya Ching; Cheng, Yu Jen; Hsieh, Kun Chou; Tsai, Lih Min; Lin, An Shen; Wu, Yang Chang^*; Yuan, Shyng Shiou

来源：Free Radical Biology and Medicine, 2011, 50(9): 1151-1162.

DOI：10.1016/j.freeradbiomed.2011.01.015

• WYC02-9
• ROS
• Prostate cancer
• gamma-H2A.X
• Delta Psi(m) decrease
• Free radicals

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.

• 出版日期2011-5-1
• 单位中国医科大学; 中山大学