Radioprotection and cell cycle arrest of intestinal epithelial cells by darinaparsin, a tumor radiosensitizer.

Abstract

PURPOSE:

It was recently reported that the organic arsenic compound darinaparsin (DPS) is a cytotoxin and radiosensitizer of tumor cells in vitro and in subcutaneous xenograft tumors. Surprisingly, it was also found that DPS protects normal intestinal crypt epithelial cells (CECs) from clonogenic death after ionizing radiation (IR). Here we tested the DPS radiosensitizing effect in a clinically relevant model of prostate cancer and explored the radioprotective effect and mechanism of DPS on CECs.

METHODS AND MATERIALS:

The radiation modification effect of DPS was tested in a mouse model of orthotopic xenograft prostate cancer and of IR-induced acute gastrointestinal syndrome. The effect of DPS on CEC DNA damage and DNA damage responses was determined by immunohistochemistry.

RESULTS:

In the mouse model of IR-induced gastrointestinal syndrome, DPS treatment before IR accelerated recovery from body weight loss and increased animal survival. DPS decreased post-IR DNA damage and cell death, suggesting that the radioprotective effect was mediated by enhanced DNA damage repair. Shortly after DPS injection, significant cell cycle arrest was observed in CECs at both G1/S and G2/M checkpoints, which was accompanied by the activation of cell cycle inhibitors p21 and growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A). Further investigation revealed that DPS activated ataxia telangiectasia mutated (ATM), an important inducer of DNA damage repair and cell cycle arrest.

CONCLUSIONS:

DPS selectively radioprotected normal intestinal CECs and sensitized prostate cancer cells in a clinically relevant model. This effect may be, at least in part, mediated by DNA damage response activation and has the potential to significantly increase the therapeutic index of radiation therapy.

• Authors: Junqiang Tian, Hiroshi Doi, Matthias Saar, Jennifer Santos, Xuejun Li, Donna M Peehl, Susan J Knox
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 87 Issue 5 Pg. 1179-85 (Dec 01 2013) ISSN: 1879-355X [Electronic] United States
• PMID: 24210080 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Arsenicals
• Radiation-Protective Agents
• Radiation-Sensitizing Agents
• darinaparsin
• Glutathione

Topics

• Animals
• Apoptosis (radiation effects)
• Arsenicals (pharmacology)
• Cell Cycle Checkpoints (drug effects)
• DNA Damage (drug effects)
• DNA Repair (drug effects)
• Duodenum (cytology, drug effects, radiation effects)
• Epithelial Cells (drug effects, radiation effects)
• Female
• Gastrointestinal Tract (drug effects, radiation effects)
• Glutathione (analogs & derivatives, pharmacology)
• Heterografts
• Humans
• Male
• Mice
• Prostatic Neoplasms (pathology, radiotherapy)
• Radiation Injuries, Experimental (drug therapy)
• Radiation Tolerance (drug effects, physiology, radiation effects)
• Radiation-Protective Agents (pharmacology)
• Radiation-Sensitizing Agents (pharmacology)
• Syndrome