Effect of a poly( ADP-ribose) polymerase-1 inhibitor against esophageal squamous cell carcinoma cell lines.

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-H2 AX 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-H2 AX 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-H2 AX was identified. Consistent with this, polyubiquitination of γ-H2 AX 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-H2 AX and sensitivity to AZD2281was observed in the TE-series cells ( R² = 0.5345). Because the assessment of basal DSB status could serve as a biomarker for selecting PARP inhibitor-tractable tumors, further investigation is warranted. [ABSTRACT FROM AUTHOR]