Colorectal cancer (CRC) is the third most common type of cancer in men and women in US. Anti-inflammatory agents have proven to be most effective in CRC prevention, but are associated with gastrointestinal toxicities. Hence, to reduce the acidic environment and enhance the chemopreventive efficacy of anti-inflammatory agent aspirin, a combination of aspirin with acidity neutralizer omeprazole was used in AOM-induced F344 Rat model of CRC. Rat (36/group) colon cancers were induced by AOM (15mg/Kg body weight) s.c., once a week for two weeks. At adenoma stage (13 wks of age), rats were fed diets containing aspirin (700 or 1400ppm), omeprazole (0, 250 or 500 ppm), or aspirin + omeprazole (700 ppm + 250 ppm; 1,400 ppm + 500 ppm). To identify a molecular predictor of the benefit of aspirin plus omeprazole we performed next-generation sequencing of colon adenocarcinomas (AdCa) treated with aspirin (1400 ppm), omeprazole (500 ppm), aspirin plus omeprazole (1400 plus 500 ppm),conducted whole-transcriptome analysis and correlated the molecular portrait with chemoprevention benefit. Aspirin plus omeprazole enhanced colon AdCa incidence inhibitory effects by 55% (p<0.0001) and multiplicity by ~87% (p<0.0001) respectively in F344 rats. Transcriptome profiling revealed 1525 hits with a 1.5-fold expression difference threshold in aspirin-treated colon AdCa (722 upregulated genes, 803 downregulated genes, P < 0.05), 1507 hits with a 1.5-fold expression difference threshold in omeprazole-treated colon AdCa (711 upregulated genes, 796 downregulated genes, P < 0.05) and 1074 hits with a 1.5-fold expression difference threshold in aspirin plus omeprazole-treated colon AdCa (662 upregulated genes, 412 downregulated genes, P < 0.05) compared to untreated colon AdCa. Multiple comparisons using Anova with samples from all groups revealed 691 hits with a 1.5-fold expression difference threshold with Benjamini Hochberg correction. Pathway analyses of these altered 691 genes indicated that the aspirin plus omeprazole treated colon AdCa upregulated cellular pathways (z score 2.26), Metabolism process (6.01) and cellular metabolic process (7.73), and downregulated signaling genes (- 8.18), signal transduction (- 8.03), immune response (- 2.08) and inflammatory response (- 2.95). A significant upregulation of Killer cell lectin-like receptor subfamily K, member 1 (natural cytotoxicity receptor which eliminates tumor cells), and acid phosphatase 2, lysosomal, (autophagy of tumor cells) was seen in the combination treatment groups compared to individual and control group AdCa. A significant decrease in TGF-β receptor signaling pathway gene SNX4 and ATPases was observed in combination treatments. Hence, these results suggest aspirin plus omeprazole combination treatments were devoid of GI toxicity increasing chemopreventive efficacy in colon cancer. Supported by NCI-N01-CN-250026

Citation Format: Naveena B. Janakiram, Altaf Mohammed, Jagan M.R. Patlolla, Yuting Zhang, Laura Biddick, Venkateshwar Madka, Li Qian, Stan Lightfoot, Barbara Dunn, Ronald Lubet, Chen S. Suen, Vernon E. Steele, Chinthalapally V. Rao. NGS Transcriptome analysis of colon adenocarcinomas treated with individual and combination of aspirin and omeprazole [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5260. doi:10.1158/1538-7445.AM2017-5260

©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.