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

Abstract

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.

• Authors: Huei-Mei Chen, Fang-Rong Chang, Ya-Ching Hsieh, Yu-Jen Cheng, Kun-Chou Hsieh, Lih-Min Tsai, An-Shen Lin, Yang-Chang Wu, Shyng-Shiou Yuan
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 50 Issue 9 Pg. 1151-62 (May 01 2011) ISSN: 1873-4596 [Electronic] United States
• PMID: 21256211 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cyclohexanones
• Flavones
• H2AX protein, human
• Histones
• Reactive Oxygen Species
• Tumor Suppressor Protein p53
• WYC02-9
• protoapigenone
• Poly(ADP-ribose) Polymerases
• Protein Kinases
• Checkpoint Kinase 2
• CHEK1 protein, human
• CHEK2 protein, human
• Checkpoint Kinase 1
• Chek1 protein, mouse
• Chek2 protein, mouse
• Protein Serine-Threonine Kinases
• Caspase 3
• Caspase 9
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Caspase 3 (genetics, metabolism)
• Caspase 9 (genetics, metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Checkpoint Kinase 1
• Checkpoint Kinase 2
• Cyclohexanones (chemical synthesis, pharmacology, therapeutic use)
• DNA Damage (drug effects)
• Flavones (chemical synthesis, pharmacology, therapeutic use)
• Gene Expression
• Histones (genetics, metabolism)
• Humans
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Nude
• Mitochondria (drug effects)
• Neoplasm Transplantation
• Neoplasms, Experimental (drug therapy, pathology)
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Protein Kinases (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)