Abstract
Abstract Aim: Tenovin-6 is one of the small molecule inhibitors of Histone Deacetylase (HDAC), which have been to shown to suppress cancer cell growth and angiogenesis. In Japan, the mortality of gastric cancer is still high and innovative strategies are required for patients with advanced unresectable gastric cancer. We conducted this study to verify anti-tumor effect of Tenovin-6 as a single agent for gastric cancer cells and also in combination with cytotoxic agents including 5-fluorouracil (5-FU) and cisplatin (CDDP) in vitro. Moreover, we validated the effectiveness of Tenovin-6 on animal xenografted model.Methods: 4 gastric cancer cell lines, MKN-45, NUGC-4 (p53 wild), NUGC-3 (p53 mutant) and Kato-III (p53 null), were incubated with Tenovin-6 in dose and time dependent manner. Cell viability was calculated by WST-8 assay after treatment with Tenovin-6 alone or in combination with 5-FU or CDDP. Protein expression of Sirt-1, p53, p21, DR5 and Caspase-3 were monitored by western blotting to reveal mechanism of antitumor effects by Tenovin-6. In vivo xenograft model established with human gastric cancer cell line MKN-45 was treated with intraperitoneal administration of Tenovin-6 at dose of 50 mg/kg/day for 2 weeks. Results: All 4 gastric cancer cells decreased dramatically by addition of Tenovin-6 with 2.3 to 4.3 μM of IC50. The decreasing trend was not different among cell lines. The additive and synergic effects were shown with combination of 5-FU or CDDP. The expression of Caspase-3, p21 and DR5 were increased by Tenovin-6 in time dependent manner. In contrast, the expression of Sirt-1 and p53 was not changed in all periods. Also in vivo, single agent therapy with Tenovin-6 significantly reduced subcutaneous xenograft tumor growth in nude mice. Conclusion: Tenovin-6 showed excellent anti-tumor effects in all gastric cancer cells via induction of apoptosis and cell cycle arrest. It may be promising therapeutic material for gastric cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4716. doi:1538-7445.AM2012-4716
Published Version
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