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

Free Radic Biol Med. 2011 May 1;50(9):1151-62. doi: 10.1016/j.freeradbiomed.2011.01.015. Epub 2011 Jan 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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