Abstract 3506: γ-secretase inhibitor enhances anti-cancer effects of 5-FU in gastric cancer

Abstract

Surgery is the most effective therapy for early gastric cancers. In advanced gastric cancer (AGC), achievement of loco-regional control after tumor resection is less successful because of frequent recurrences after surgical and medical therapies. Combinations of 5-fluorouracil (5-FU) and platinum analogues or cytotoxic agents, such as capecitabine, cisplastin, oxaliplatin and S-1, are currently widely accepted as standard treatment for AGC. However, survival of AGC patients following sedative chemotherapy is poor. Therefore, the development of novel therapies has been needed, and some clinical studies already have been performed using novel molecular targeting agents have shown hopeful activity, particularly in combination with cytotoxic agents. Recently, the importance of Notch signal pathway has been reported in gastric cancer. Gamma-secretase inhibitors (GSI), a notch proteolytic activation blocker, can be considered as a novel target agent for gastric cancer. In this study, the anti-proliferation effects of GSI combined with 5-FU on gastric cancer cells in vitro and in vivo were studied. GSI combined with 5-FU was treated on gastric cancer cells, and then cell-proliferation by MTT assay, apoptosis by annexin V and expressions of protein level were determined by western blotting. Effects of GSI combined with 5-FU on tumor growth in vivo was assessed in an experimental model with orthotopically grown tumors. In gastric cancer cells, GSI combined with 5FU significantly inhibited cell proliferation and induced apoptosis. It was confirmed by expression changes of apoptosis related protein, such as caspase-3, caspase-8, caspase-9, PARP, BCL2, BID and BAX. GSI is also known to regulate PI3K/PTEN/AKT signaling pathway. After treatment with GSI plus 5-FU, this pathway was significantly down-regulated, and more, over-expression of constitutively activated AKT could prevent the apoptosis induction by combination treatment. This is suggested that the combination treatment with GSI plus 5-FU decreases the gastric cancer cell growth through inhibition of PI3K/PTEN/AKT signaling pathway. Moreover, administration of GSI in combination with 5-FU drastically reduced gastric tumor burdens in orthografted mice without prominent gastrointestinal toxicity. In conclusion, we present here that the combination treatment with GSI plus 5-FU has a potential for therapeutic activity in advanced gastric cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3506. doi:10.1158/1538-7445.AM2011-3506