RRC ID 44731
Author Nasuno T, Mimaki S, Okamoto M, Esumi H, Tsuchihara K.
Title Effect of a poly(ADP-ribose) polymerase-1 inhibitor against esophageal squamous cell carcinoma cell lines.
Journal Cancer Sci.
Abstract Effective molecular target drugs that improve therapeutic efficacy with fewer adverse effects for esophageal cancer are highly anticipated. Poly(ADP-ribose) polymerase (PARP) inhibitors have been proposed as low-toxicity agents to treat double strand break (DSB)-repair defective tumors. Several findings imply the potential relevance of DSB repair defects in the tumorigenesis of esophageal squamous cell carcinoma (ESCC). We evaluated the effect of a PARP Inhibitor (AZD2281) on the TE-series ESCC cell lines. Of these eight cell lines, the clonogenic survival of one (TE-6) was reduced by AZD2281 to the level of DSB repair-defective Capan-1 and HCC1937 cells. AZD2281-induced DNA damage was implied by increases in γ-H2AX and cell cycle arrest at G2/M phase. The impairment of DSB repair in TE-6 cells was suggested by a sustained increase in γ-H2AX levels and the tail moment calculated from a neutral comet assay after X-ray irradiation. Because the formation of nuclear DSB repair protein foci was impaired in TE-6 cells, whole-exome sequencing of these cells was performed to explore the gene mutations that might be responsible. A novel mutation in RNF8, an E3 ligase targeting γ-H2AX was identified. Consistent with this, polyubiquitination of γ-H2AX after irradiation was impaired in TE-6 cells. Thus, AZD2281 induced growth retardation of the DSB repair-impaired TE-6 cells. Interestingly, a strong correlation between basal expression levels of γ-H2AX and sensitivity to AZD2281was observed in the TE-series cells (R(2)  = 0.5345). Because the assessment of basal DSB status could serve as a biomarker for selecting PARP inhibitor-tractable tumors, further investigation is warranted.
Volume 105(2)
Pages 202-10
Published 2014-2
DOI 10.1111/cas.12322
PMID 24219164
PMC PMC4317825
MeSH Carcinoma, Squamous Cell / drug therapy* Carcinoma, Squamous Cell / enzymology Carcinoma, Squamous Cell / genetics Carcinoma, Squamous Cell / metabolism Cell Cycle Checkpoints / drug effects Cell Division / drug effects Cell Line, Tumor DNA Damage / drug effects DNA Repair / drug effects DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Esophageal Neoplasms / drug therapy* Esophageal Neoplasms / enzymology Esophageal Neoplasms / genetics Esophageal Neoplasms / metabolism Esophageal Squamous Cell Carcinoma G2 Phase / drug effects Histones / genetics Histones / metabolism Humans MCF-7 Cells Molecular Sequence Data Mutation / drug effects Mutation / genetics Phthalazines / adverse effects Phthalazines / pharmacology* Piperazines / adverse effects Piperazines / pharmacology* Poly(ADP-ribose) Polymerase Inhibitors* Ubiquitin-Protein Ligases
IF 4.372
Times Cited 6
Human and Animal Cells