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 omeprazole-administered 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/pro-survival 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. Prevention Relevance: Preventing colon cancer is urgently needed because of its high incidence and mortality rates worldwide. Toward this end, preventive efficacy of omeprazole, a common medication, was evaluated in animal model of colorectal cancer and was found to suppress colonic adenoma progression to carcinoma. These findings warrant its further evaluation in humans.

中文翻译：

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质子泵抑制剂奥美拉唑抑制 F344 大鼠致癌物诱导的结肠腺瘤进展为腺癌

在美国，结直肠癌每年导致超过 53,000 人死亡。它在世界范围内的发病率不断上升，特别是在年轻人中，这是一个主要问题。在这里，我们评估了临床批准用于治疗胃酸反流的奥美拉唑的功效，以使其能够重新用于预防结直肠癌。在偶氮甲烷诱导的大鼠结肠直肠癌模型中，在早期腺瘤阶段（偶氮甲烷后 8 周）给予饮食奥美拉唑（250 和 500 ppm），以评估早期病变向腺癌的进展。给予 250 或 500 ppm 剂量的奥美拉唑可分别抑制 15.7% 和 32% 的总结肠腺癌发病率（P < 0.01）。重要的是，浸润癌发病率降低了 59%（P < 0.0005）和 90%（P < 0. 0001）在奥美拉唑给药的大鼠中以剂量依赖性方式。在暴露于奥美拉唑的大鼠中，对腺癌多样性也有强烈的和剂量依赖性的抑制作用。施用 250 和 500 ppm 奥美拉唑分别抑制了约 49% 和约 65% 的总结肠腺癌多样性（P < 0.0001）。与未经治疗的大鼠相比，奥美拉唑暴露大鼠的非侵袭性腺癌多样性被抑制了大约 34% 至大约 48% ( P < 0.02)，而浸润性癌的多样性降低了大约 74% 至大约 94% ( P < 0.0001) . 生物标志物分析结果显示细胞增殖和抗凋亡/促存活蛋白减少，细胞凋亡增加。治疗肿瘤的转录组分析显示腺癌抑制基因（Olmf4；Spink4）表达显着增加，进展促进基因（SerpinA1、MMP21、IL6）下调。总之，奥美拉唑对腺瘤进展为腺癌显示出显着的保护作用。预防相关性：由于结肠癌在世界范围内的高发病率和死亡率，迫切需要预防结肠癌。为此，在结直肠癌动物模型中评估了常用药物奥美拉唑的预防效果，发现其可抑制结肠腺瘤进展为癌。这些发现保证了它在人类身上的进一步评估。奥美拉唑对腺瘤进展为腺癌显示出显着的保护作用。预防相关性：由于结肠癌在世界范围内的高发病率和死亡率，迫切需要预防结肠癌。为此，在结直肠癌动物模型中评估了常用药物奥美拉唑的预防效果，发现其可抑制结肠腺瘤进展为癌。这些发现保证了它在人类身上的进一步评估。奥美拉唑对腺瘤进展为腺癌显示出显着的保护作用。预防相关性：由于结肠癌在世界范围内的高发病率和死亡率，迫切需要预防结肠癌。为此，在结直肠癌动物模型中评估了常用药物奥美拉唑的预防效果，发现其可抑制结肠腺瘤进展为癌。这些发现保证了它在人类身上的进一步评估。在结直肠癌的动物模型中进行了评估，发现它可以抑制结肠腺瘤进展为癌。这些发现保证了它在人类身上的进一步评估。在结直肠癌的动物模型中进行了评估，发现它可以抑制结肠腺瘤进展为癌。这些发现保证了它在人类身上的进一步评估。