Abstract 2820: Omeprazole alone, or in combination with Aspirin inhibits azoxymethane-induced colon adenoma progression to adenocarcinoma and carcinoma invasion in F344 rat model
Authors: Mohammed Altaf , Patlolla Jagan M.R , Zhang Yuting , Biddick Laura , Madka Venkateshwar , Li Qian , Lightfoot Stan , Lubet Ronald , Suen Chen S. , Steele Vernon E. , Rao Chinthalapally V. 
Published: August 2015

Colorectal Cancer (CRC) is a major public health issue world-wide with an estimated over 600,000 deaths annually. Aspirin and Omeprazole are most commonly used medications. Aspirin has been proven as CRC chemopreventive agent, but its usage is limited by GI toxicity. The rationale to establish the chemopreventive role of Omeprazole has been based on i) acidic tumor environment due to the Warburg-effect, and ii) it may protect from the GI toxicity induced by aspirin. Male F344 rats were used to establish omeprazole and aspirin optimal doses, efficacy, dose-response effects of combinations. Rat (36-42 animals per group) colon cancers were induced by two weekly dose of AOM. At adenoma stage, rats were fed diets containing Omeprazole (0, 250 or 500 ppm), or aspirin + omeprazole (700 ppm + 250 ppm; 1,400 ppm + 500 ppm; 2,800 ppm + 250 ppm, respectively) and a combination dose fed every three weeks on and off. All rats were euthanized 48 weeks after AOM treatment and assessed for efficacy, dose-response effects and various biomarkers in colonic tissues. Dietary administration of test agents alone or combinations did not show any overt-toxicities. Administration of 250 and 500 ppm omeprazole inhibited colon adenocarcinoma incidence by 15.7% and 32% (p&lt;0.01) and multiplicity by 49% (p&lt;0.0001) and 65% (p&lt;0.0001), respectively; importantly, colon invasive carcinoma incidence was reduced by 59% and 90% (p&lt;0.0001) and multiplicity by 74% and 93% (p&lt;0.0001), respectively. However, we observed a modest decrease in total colonic tumors with a significant increase in adenomas. Continuous administration of above combinations showed inhibition of adenocarcinoma incidences by 41% (p&lt;0.001), 55% (p&lt;0.0001) and 74% (p&lt;0.0001) and multiplicities by 74%, 76% and 87% (p&lt;0.0001). Interestingly, intermittent dosing of combinations did not diminish inhibition of CRC incidence or multiplicity. Furthermore, omeprazole alone or combining with aspirin showed &gt;90% inhibition of invasive adenocarcinomas. In tumors of rats fed omeprazole alone or in combination with aspirin, there was a significant decrease in markers of proliferation (PCNA and β-catenin) and increase in apoptosis (p53, p21, Annexin V) when compared with CRC of rats fed control diet. Surprisingly, we observed a dramatic decrease in the expression levels of proton pump (K+-, H+- ATPase) markers in colonic tumors as compared to tumor adjacent mucosa. These results suggest that omeprazole tumor inhibitory mechanism may not be dependent on tumor proton pump inhibition. Overall, our results suggest that Omeprazole had significant dose-response efficacy effects on the adenoma progression to adenocarcinomas; particularly invasive carcinomas and combining with aspirin significantly enhanced adenocarcinoma inhibitory effects. {This work was supported by NCI-N01-CN-250026}

Citation Format: Altaf Mohammed, Jagan M.R Patlolla, Yuting Zhang, Laura Biddick, Venkateshwar Madka, Qian Li, Stan Lightfoot, Ronald Lubet, Chen S. Suen, Vernon E. Steele, Chinthalapally V. Rao. Omeprazole alone, or in combination with Aspirin inhibits azoxymethane-induced colon adenoma progression to adenocarcinoma and carcinoma invasion in F344 rat model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2820. doi:10.1158/1538-7445.AM2015-2820