Targeted radiosensitization by the Chk1 inhibitor SAR-020106

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

doi:10.1016/j.ijrobp.2012.08.006

Targeted radiosensitization by the Chk1 inhibitor SAR-020106

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

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1110-8
Number of pages	9
Journal	International journal of radiation oncology, biology, physics
Volume	85
Issue number	4
DOIs	https://doi.org/10.1016/j.ijrobp.2012.08.006
Publication status	Published - 15 Mar 2013

Keywords

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

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ijrobp.2012.08.006

Cite this

Borst, G. R., McLaughlin, M., Kyula, J. N., Neijenhuis, S., Khan, A., Good, J., Zaidi, S., Powell, N. G., Meier, P., Collins, I., Garrett, M. D., Verheij, M., & Harrington, K. J. (2013). Targeted radiosensitization by the Chk1 inhibitor SAR-020106. International journal of radiation oncology, biology, physics, 85(4), 1110-8. https://doi.org/10.1016/j.ijrobp.2012.08.006

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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.",

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

author = "Borst, {Gerben R} and Martin McLaughlin and Kyula, {Joan N} and Sari Neijenhuis and Aadil Khan and James Good and Shane Zaidi and Powell, {Ned G} and Pascal Meier and Ian Collins and Garrett, {Michelle D} and Marcel Verheij and Harrington, {Kevin J}",

year = "2013",

month = mar,

day = "15",

doi = "10.1016/j.ijrobp.2012.08.006",

language = "English",

volume = "85",

pages = "1110--8",

journal = "International journal of radiation oncology, biology, physics",

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T1 - Targeted radiosensitization by the Chk1 inhibitor SAR-020106

AU - Borst, Gerben R

AU - McLaughlin, Martin

AU - Kyula, Joan N

AU - Neijenhuis, Sari

AU - Khan, Aadil

AU - Good, James

AU - Zaidi, Shane

AU - Powell, Ned G

AU - Meier, Pascal

AU - Collins, Ian

AU - Garrett, Michelle D

AU - Verheij, Marcel

AU - Harrington, Kevin J

PY - 2013/3/15

Y1 - 2013/3/15

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis

KW - Cell Cycle/drug effects

KW - Cell Line, Tumor

KW - Checkpoint Kinase 1

KW - Cyclin-Dependent Kinase Inhibitor p21/deficiency

KW - DNA Damage/drug effects

KW - DNA Repair/drug effects

KW - G2 Phase/drug effects

KW - HeLa Cells

KW - Histones/analysis

KW - Humans

KW - Immunohistochemistry/methods

KW - Isoquinolines/pharmacology

KW - Mice

KW - Mice, Nude

KW - Microscopy/methods

KW - Mitosis/drug effects

KW - Papillomaviridae/classification

KW - Protein Kinases/drug effects

KW - Pyrazines/pharmacology

KW - Radiation Tolerance/drug effects

KW - Radiation-Sensitizing Agents/pharmacology

KW - Time-Lapse Imaging/methods

KW - Tumor Stem Cell Assay/methods

KW - Tumor Suppressor Protein p53/deficiency

U2 - 10.1016/j.ijrobp.2012.08.006

DO - 10.1016/j.ijrobp.2012.08.006

M3 - Article

C2 - 22981708

SN - 0360-3016

VL - 85

SP - 1110

EP - 1118

JO - International journal of radiation oncology, biology, physics

JF - International journal of radiation oncology, biology, physics

IS - 4

ER -

Targeted radiosensitization by the Chk1 inhibitor SAR-020106

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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