Riccardin D Exerts Its Antitumor Activity by Inducing DNA Damage in PC-3 Prostate Cancer Cells In Vitro and In Vivo.

Abstract

We recently reported that Riccardin D (RD) was able to induce apoptosis by targeting Topo II. Here, we found that RD induced cell cycle arrest in G2/M phase in PC-3 cells, and caused remarkable DNA damage as evidenced by induction of γH2AX foci, micronuclei, and DNA fragmentation in Comet assay. Time kinetic and dose-dependent studies showed that ATM/Chk2 and ATR/Chk1 signaling pathways were sequentially activated in response to RD. Blockage of ATM/ATR signaling led to the attenuation of RD-induced γH2AX, and to the partial recovery of cell proliferation. Furthermore, RD exposure resulted in the inactivation of BRCA1, suppression of HR and NHEJ repair activity, and downregulation of the expressions and DNA-end binding activities of Ku70/86. Consistent with the observations, microarray data displayed that RD triggered the changes in genes responsible for cell proliferation, cell cycle, DNA damage and repair, and apoptosis. Administration of RD to xenograft mice reduced tumor growth, and coordinately caused alterations in the expression of genes involved in DNA damage and repair, along with cell apoptosis. Thus, this finding identified a novel mechanism by which RD affects DNA repair and acts as a DNA damage agent in prostate cancer.

• Authors: Zhongyi Hu, Feng Kong, Manfei Si, Keli Tian, Lin Xi Yu, Charles Y F Young, Huiqing Yuan, Hongxiang Lou
• Journal: PloS one (PLoS One) Vol. 8 Issue 9 Pg. e74387 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24069304 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Nuclear
• Antineoplastic Agents, Phytogenic
• DNA-Binding Proteins
• Phenyl Ethers
• Stilbenes
• riccardin D
• Protein Kinases
• Checkpoint Kinase 2
• Ataxia Telangiectasia Mutated Proteins
• CHEK1 protein, human
• Checkpoint Kinase 1
• Chek1 protein, mouse
• Xrcc6 protein, human
• Xrcc6 protein, mouse
• Ku Autoantigen

Topics

• Animals
• Antigens, Nuclear (genetics, metabolism)
• Antineoplastic Agents, Phytogenic (pharmacology, toxicity)
• Apoptosis (drug effects)
• Ataxia Telangiectasia Mutated Proteins (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Checkpoint Kinase 1
• Checkpoint Kinase 2 (metabolism)
• DNA Damage (drug effects)
• DNA End-Joining Repair (drug effects)
• DNA-Binding Proteins (genetics, metabolism)
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic
• Humans
• Ku Autoantigen
• Male
• Mice
• Phenyl Ethers (pharmacology, toxicity)
• Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Protein Kinases (metabolism)
• Recombinational DNA Repair (drug effects)
• Signal Transduction
• Stilbenes (pharmacology, toxicity)
• Transcriptome
• Xenograft Model Antitumor Assays