Abstract 4983: Intermittent dosing regimens of naproxen and aspirin inhibit azoxymethane-induced rat colon adenoma progression to adenocarcinoma and carcinoma invasion
Authors: Mohammed Altaf , Janakiram Naveena B. , Madka Venkateshwar , Zhang Yuting , Singh Anil , Biddick Laura , Li Qian , Lightfoot Stan , Steele Vernon E. , Lubet Ronald , Miller Mark S. , Suen Chen S. , Sei Shizuko , Rao Chinthalapally V. 
Published: August 2018

Colorectal Cancer (CRC) is a major public health issue world-wide with an estimated 700,000 deaths annually. Adults 50 to 69 years of age considered high-risk for CRC can take low-dose Aspirin daily for at least 10 years to reduce their risk for CRC, according to a set of recommendations from the US Preventive Services Task Force. Naproxen is a highly efficacious CRC chemopreventive agent in animal models. Continuous/chronic usage of both drugs is limited by GI toxicity and unwanted side effects. Thus, the rationale to establish intermittent dosing regimens of Naproxen and Aspirin may provide efficacy without GI toxicity. Male F344 rats were used to establish Naproxen and Aspirin pharmacodynamic efficacy and dose-response effects. Rat (36 animals/group) colon cancers were induced by two weekly doses of azoxymethane (AOM). At the adenoma stage, rats were fed diets containing Naproxen (200 and 400 ppm) or Aspirin (700, and 1,400 ppm) either continuously, 1 week on/1 week off, or 3 weeks on/3 weeks off, or Aspirin (2,800 ppm) 3 weeks on/3 weeks off. All rats were euthanized 48 weeks after AOM treatment and assessed for efficacy, dose-response effects, and biomarkers in tumor tissues. Dietary administration of Naproxen and Aspirin did not show any overt-toxicities. Administration of 200 and 400 ppm of Naproxen inhibited colon adenocarcinoma multiplicity by 54.5% and 70.5% (p&lt;0.0001) (continuous treatment); 53.3% and 68.4% (p&lt;0.0001) (1 week on/1 week off); and 22.5% (p&lt;0.03) and 61.5% (p&lt;0.0001) (3 weeks on/3 weeks off), respectively. Importantly, inhibition of invasive colon carcinoma was reduced by 53% (p&lt;0.0009) - &gt;88% (p&lt;0.0001) with different treatment regimens of Naproxen. With regard to colon adenocarcinoma multiplicity, Aspirin showed significant inhibitory effect with different treatment regimens with clear dose-response effects. Total adenocarcinomas (both invasive and non-invasive) multiplicities were suppressed by 41% (P&lt;0.003) - 72% (p&lt;0.0001). Particularly, Aspirin showed suppression of invasive colon adenocarcinomas by &gt;67% (p&lt;0.0001) - &gt;91% (p&lt;0.0001) with different treatment regimens. Based on the biomarkers of proliferation and apoptosis, both agents showed significant modulation of proliferative (PCNA, p21) and apoptotic markers (p53, Casp3) in colonic tumors. Transcriptomic data revealed that proinflammatory cytokines, particularly interleukins and metalloproteases, were significantly reduced in tumors of rats exposed to Aspirin and Naproxen. Overall, our results suggest that intermittent dosing with Naproxen or Aspirin demonstrated significant dose-response efficacy on the progression of adenomas to adenocarcinomas, particularly invasive carcinomas. {This work was supported by NCI-N01-CN-250026}

Citation Format: Altaf Mohammed, Naveena B. Janakiram, Venkateshwar Madka, Yuting Zhang, Anil Singh, Laura Biddick, Qian Li, Stan Lightfoot, Vernon E. Steele, Ronald Lubet, Mark S. Miller, Chen S. Suen, Shizuko Sei, Chinthalapally V. Rao. Intermittent dosing regimens of naproxen and aspirin inhibit azoxymethane-induced rat colon adenoma progression to adenocarcinoma and carcinoma invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4983.