Proton pump inhibitor omeprazole suppresses carcinogen-induced colonic adenoma progression to adenocarcinoma in F344 rat

Venkateshwar Madka, Gaurav Kumar, Gopal Pathuri, Janani Panneerselvam, Yuting Zhang, Vishal Ganta, Stanley Lightfoot, Ronald Lubet, Chen S. Suen, Vernon E. Steele, Naveena B. Janakiram, Altaf Mohammed, Chinthalapally V. Rao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Colorectal cancer causes over 53,000 deaths annually in the United States. Its rising incidences worldwide and particularly in young adults is a major concern. Here, we evaluated the efficacy of omeprazole that is clinically approved for treating acid reflux, to enable its repurposing for colorectal cancer prevention. In the azoxymethane-induced rat colorectal cancer model, dietary omeprazole (250 and 500 ppm) was administered at early adenoma stage (8 weeks after azoxymethane) to assess the progression of early lesions to adenocarcinoma. Administration of omeprazole at 250 or 500 ppm doses led to suppression of total colon adenocarcinoma incidence by 15.7% and 32% (P < 0.01), respectively. Importantly, invasive carcinoma incidence was reduced by 59% (P < 0.0005) and 90% (P < 0.0001) in omeprazoleadministered rats in a dose-dependent manner. There was also a strong and dose-dependent inhibition in the adenocarcinoma multiplicity in rats exposed to omeprazole. Administration of 250 and 500 ppm omeprazole inhibited total colon adenocarcinoma multiplicity by approximately 49% and approximately 65% (P < 0.0001), respectively. While noninvasive adenocarcinomas multiplicity was suppressed by approximately 34% to approximately 48% (P < 0.02), the invasive carcinomas multiplicity was reduced by approximately 74% to approximately 94% (P < 0.0001) in omeprazole-exposed rats in comparison with the untreated rats. Biomarker analysis results showed a decrease in cell proliferation and anti-apoptotic/prosurvival proteins with an increase in apoptosis. Transcriptome analysis of treated tumors revealed a significant increase in adenocarcinoma inhibitory genes (Olmf4; Spink4) expression and downregulation of progression promoting genes (SerpinA1, MMP21, IL6). In summary, omeprazole showed significant protection against the progression of adenoma to adenocarcinoma.

Original languageEnglish
Pages (from-to)1009-1019
Number of pages11
JournalCancer Prevention Research
Volume14
Issue number11
DOIs
StatePublished - Nov 2021
Externally publishedYes

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