Abstract 5338: Preclinical study of telomerase-specific p53 tumor suppressor gene overexpression in human scirrhous gastric cancer cells with different p53 status

Abstract

Abstract Background: Despite multimodal therapy for scirrhous gastric cancer, many patients show refractory to conventional therapy and rapid progression, leading to poor prognosis. Therefore, the development of novel therapeutic strategy is required to improve the clinical outcome in patients with scirrhous gastric cancers. As novel therapeutic strategies, Ad-p53, a replication-defective adenovirus expressing a tumor suppressor p53 gene, is currently under clinical evaluation for various types of cancers. We recently developed a novel p53-expressing telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces the p53 gene expression in a telomerase-dependent manner. In this study, we investigated the antitumor effects of Ad-p53 and OBP-702 in human scirrhous gastric cancer cells with different p53 status. Methods: We used 3 human scirrhous gastric cancer cell lines with different p53 status, NUGC4 (p53 wild-type), GCIY (p53 mutant-type), and KATOIII (p53 null). The antitumor effects of Ad-p53 and OBP-702 were evaluated using XTT assay. The 50% inhibiting dose (ID50) value of Ad-p53 and OBP-702 for each cell was calculated using cell viability data obtained 3 days after virus infection. We evaluated the virus-mediated cell death in the sphere-forming cells by LIVE/DEAD assay. The apoptosis- and autophagy-related cell death was assessed by western blot analysis for cleaved poly (ADP-ribose) polymerase (PARP) and p62. Results: Ad-p53 suppressed the cell viability in p53-inactivated scirrhous gastric cancer cells (KATO III, GCIY), whereas p53-intact NUGC4 cells were resistant to Ad-p53. OBP-702 efficiently suppressed the cell viability in all scirrhous gastric cancer cells with different p53 function. The ID50 value of OBP-702 was lower than that of Ad-p53 in all cell lines. LIVE/DEAD assay showed that OBP-702 induced cell death more efficiently than Ad-p53 in the sphere-forming cells. OBP-702 induced more profound p53 expression and apoptotic cell death than Ad-p53. Moreover, only OBP-702 induced not only apoptosis but also autophagy. Conclusions: These results suggest that p53-expressing tumor-specific oncolytic adenovirus OBP-702 is a promising antitumor agent to induce profound cell death in scirrhous gastric cancers with different p53 status. Now, in vivo experiments are under way to investigate the antitumor effect of OBP-702 in the peritoneal dissemination of scirrhous gastric cancer cells. Citation Format: Naoto Hori, Hiroshi Tazawa, Masahiko Nishizaki, Satoru Kikuchi, Shuya Yano, Michihiro Ishida, Megumi Watanabe, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara. Preclinical study of telomerase-specific p53 tumor suppressor gene overexpression in human scirrhous gastric cancer cells with different p53 status. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5338. doi:10.1158/1538-7445.AM2015-5338