Abstract 15: Hypertension drug Olmesartan medoxomil promotes colonic tumorigenesis in AOM-induced CRC rat model

Abstract

Abstract Some retrospective studies suggest an inverse risk-association between the use of angiotensin signaling inhibitors and colorectal cancer (CRC). The angiotensin receptor blocker olmesartan medoxomil (OLM) is commonly prescribed for hypertension treatment. Here we sought to determine the chemopreventive efficacy of OLM using the azoxymethane (AOM)-induced CRC rat model. Male and female F344 rats (n=6/gender/group) were randomized and subcutaneously injected with 20 mg/kg of AOM once weekly for two weeks. One week later, AIN76-A diets containing OLM (0 ppm to 480 ppm) were fed to rats. Six weeks after treatment, rats were euthanized and evaluated for toxicity and aberrant crypt foci (ACF) inhibition. OLM-fed rats, particularly at ≥160 ppm, showed signs of toxicity. There was a modest decrease in the total ACFs without any change in multicrypt ACFs in male rats; however in females there was an increase in multicrypt ACFs as compared to the control diet group. For tumor efficacy evaluation, 5-week-old F344 rats were randomized (n=30/gender/group) and CRC was induced as described above. At the adenoma stage (12-weeks after AOM-treatment), rats were administered OLM (0, 20 and 40 ppm) in the diet for 33 weeks, and colonic tumors were evaluated. In the control group, there was a huge disparity in colonic tumor incidence and multiplicity between genders with ~3-fold less tumors in female rats. Surprisingly, colon tumor incidence was significantly increased (3-fold; p<0.0002) in the OLM-treated female rats (77% OLM vs 24% control). Colon tumor multiplicity analysis also showed tumor promoting effects. In the 20 ppm OLM-treated male and female rats, colonic adenocarcinoma multiplicities were increased by ~91% (p<0.01) and ~362% (p<0.0001), respectively, when compared with their respective controls. Although there was no dose response, similar tumor promoting effects were found in 40 ppm OLM-treated rats. To understand male vs female colon tumor disparities and OLM tumor promoting effects, we carried out RNA-Seq analysis of colonic tumors. Reflecting tumor data, gene expression analysis also showed significant differences between male and female rats with respect to type II-interferon, PI3K-AKT, cholesterol, lipid droplet, mucin, IL-3, cell-cycle and nucleotide GPCR signaling pathways. OLM treatment significantly upregulated 586 and 740 genes, and downregulated 648 and 564 genes in male and female rat tumors, respectively. Of the 293 common genes identified, Irx5, Lrrn1, Ly6g6e, Sccpdh, Hoxd12, Igfbp1, Krt81 and DSC3 were upregulated up to 245-fold; and Rfxapl1, Serpinb3a, REg3b, Bnc1 and Ak4 were down-regulated 10 - 200-fold with OLM treatment. In conclusion, chronic administration of OLM did not provide any chemopreventive benefit against colonic tumors in the AOM-induced F344 rat CRC model. Further studies are warranted to assess the risk of colon cancer associated with long-term OLM use, particularly in females. (Supported by NCI HHSN 261201500038I and VA Merit Award) Citation Format: Venkateshwar Madka, Yuting Zhang, Gopal Pathuri, Janani Panneerselvam, Nicole Stratton, Anil Singh, Shizuko Sei, Jennifer Fox, Chinthalapally V. Rao. Hypertension drug Olmesartan medoxomil promotes colonic tumorigenesis in AOM-induced CRC rat model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 15.