Abstract 1858: Inhibition of oral carcinogenesis in rats by the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA)

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Suberoylanilide hydroxamic acid (SAHA; N-hydroxy-N′-phenyl-octanediamide; vorinostat) is a potent inhibitor of cell proliferation, inducer of cellular differentiation, and inducer of apoptosis in cancer cells. The anticancer action of SAHA is likely to result from its activity as an inhibitor of histone deacetylase, which mediates alterations in the expression of cancer-associated genes. SAHA has been shown to be an effective inhibitor of carcinogenesis in animal models for breast, lung, and colon cancer; the present study was performed to evaluate the activity of SAHA as an inhibitor of oral carcinogenesis. Squamous cell carcinomas of the tongue were induced in male F344 rats by administration of 4-nitroquinoline-1-oxide (NQO; 20 ppm) in the drinking water for 10 weeks. After completion of NQO administration, rats were randomized into groups of 25 and received either unsupplemented basal diet (dietary control); basal diet supplemented with SAHA (500 mg/kg diet); or basal diet supplemented with SAHA (1000 mg/kg diet). All experimental diets were fed continuously until the end of the study at week 26. Dietary administration of SAHA induced a dose-related reduction in oral cancer incidence (64% and 29% in the low and high dose groups, respectively, versus 80% in the dietary control group; p < 0.01). In addition, the high dose of SAHA increased the percentage of animals without any evidence of oral pathology from 4% in dietary controls to 25% (p < 0.05). In addition to its effects on cancer incidence, SAHA reduced the invasiveness of induced oral cancers in NQO-treated rats: whereas 60% of rats in the dietary control group demonstrated advanced oral cancers (invasion scores of +3 or +4), advanced cancers were seen in 40% and 25% of rats fed the low and high doses of SAHA, respectively (p < 0.05 for high dose). SAHA increased the incidence of squamous epithelial hyperplasia (28% and 38% in low and high dose groups, respectively, versus 16% in dietary controls; p < 0.05 for high dose). This effect suggests that SAHA prevented the progression of hyperplastic lesions into invasive oral cancers. SAHA also prevented the body weight loss that is commonly seen in this model in animals with advanced oral cancer. These data demonstrate SAHA is a potent inhibitor of carcinogen-induced squamous cell carcinoma in rats, and suggest that inhibitors of histone deacetylase should be considered for further development as inhibitors of oral cancer development. (Supported by N01-CN-25113 from the NCI.) 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 1858. doi:10.1158/1538-7445.AM2011-1858