Targeted radiosensitization by the Chk1 inhibitor SAR-020106.

Abstract

PURPOSE:

To explore the activity of a potent Chk1 inhibitor (SAR-020106) in combination with radiation.

METHODS AND MATERIALS:

Colony and mechanistic in vitro assays and a xenograft in vivo model.

RESULTS:

SAR-020106 suppressed-radiation-induced G2/M arrest and reduced clonogenic survival only in p53-deficient tumor cells. SAR-020106 promoted mitotic entry following irradiation in all cell lines, but p53-deficient cells were likely to undergo apoptosis or become aneuploid, while p53 wild-type cells underwent a postmitotic G1 arrest followed by subsequent normal cell cycle re-entry. Following combined treatment with SAR-020106 and radiation, homologous-recombination-mediated DNA damage repair was inhibited in all cell lines. A significant increase in the number of pan-γH2AX-staining apoptotic cells was observed only in p53-deficient cell lines. Efficacy was confirmed in vivo in a clinically relevant human head-and-neck cell carcinoma xenograft model.

CONCLUSION:

The Chk1 inhibitor SAR-020106 is a potent radiosensitizer in tumor cell lines defective in p53 signaling.

• Authors: Gerben R Borst, Martin McLaughlin, Joan N Kyula, Sari Neijenhuis, Aadil Khan, James Good, Shane Zaidi, Ned G Powell, Pascal Meier, Ian Collins, Michelle D Garrett, Marcel Verheij, Kevin J Harrington
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 85 Issue 4 Pg. 1110-8 (Mar 15 2013) ISSN: 1879-355X [Electronic] United States
• PMID: 22981708 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• H2AX protein, human
• Histones
• Isoquinolines
• Pyrazines
• Radiation-Sensitizing Agents
• SAR 020106
• Tumor Suppressor Protein p53
• Protein Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1
• Chek1 protein, mouse

Topics

• Animals
• Apoptosis
• Cell Cycle (drug effects, genetics, radiation effects)
• Cell Line, Tumor
• Checkpoint Kinase 1
• Cyclin-Dependent Kinase Inhibitor p21 (deficiency)
• DNA Damage (drug effects, genetics)
• DNA Repair (drug effects, genetics, radiation effects)
• G2 Phase (drug effects, genetics)
• HeLa Cells
• Histones (analysis)
• Humans
• Immunohistochemistry (methods)
• Isoquinolines (pharmacology)
• Mice
• Mice, Nude
• Microscopy (methods)
• Mitosis (drug effects, radiation effects)
• Papillomaviridae (classification)
• Protein Kinases (drug effects)
• Pyrazines (pharmacology)
• Radiation Tolerance (drug effects, genetics, radiation effects)
• Radiation-Sensitizing Agents (pharmacology)
• Time-Lapse Imaging (methods)
• Tumor Stem Cell Assay (methods)
• Tumor Suppressor Protein p53 (deficiency)