Abstract 2139: Pre-clinical chemopreventive efficacy of a novel hybrid p-XSC-aspirin compound in a NNK-induced A/J mouse lung cancer model

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Despite the identification of several preventive agents and strategies, prevention of lung cancer, especially in smokers who are at high risk, is still largely unattained. 1,4-Phenylenebis(methylene)selenocyanate (p-XSC) has been shown to inhibit tobacco carcinogen NNK induced lung cancer development in several animal models. It metabolizes through the formation of active bis-selenol (p-XSeH) along with the release of poisonous hydrogen cyanide (HCN). Nevertheless, the HCN released upon metabolism of p-XSC to form active metabolite p-XSeH, pose a serious challenge its clinical use in a chemopreventive set up where a continuous intake is required for healthy individuals over a longer period of time. Recently, we developed a hybrid agent, p-XS-Asp, linking p-XSe- to commonly used non-steroidal anti-inflammatory drug, aspirin (Asp), which has been shown to be preventive of lung, and colorectal cancer. We hypothesized that p-XS-Asp would cleave in vivo to release the active p-XSeH, not releasing undesired HCN but the aspirin, thus making the compound less toxic and more potent than p-XSC or aspirin alone. Our studies have shown p-XS-Asp to be orally bioavailable and a highly effective lung cancer chemopreventive agent both in vitro and in animal studies. Elemental selenium (Se) analysis of plasma, lung, and liver tissue in orally fed mice showed that the level of Se significantly higher for p-XS-Asp than p-XSC, denoting a better bioavailability profile for p-XS-Asp. Dietary p-XS-Asp inhibited both O-6 methyl guanine and pyridoxobutyl (pob) DNA adducts, in lung and liver of A/J mice, more effectively than p-XSC. Particularly, in the lung, the inhibition of O-6 methyl guanine adducts, which are critical for A/J mouse lung tumor development, were more than 2 times higher than p-XSC. In a NNK-induced lung cancer A/J mouse model, p-XS-Asp at doses of 15 ppm and 7.5 ppm Se, showed a significantly marked decrease in percentage of lung tumor incidence of 50% and 87%, as compared to p-XSC (79% and 100%), respectively; NNK-control showed an 100% tumor incidence. In addition, the multiplicity for p-XS-Asp was 0.87 and 1.93 tumors/mouse as compared with NNK-control (11.53 tumors/mouse) and p-XSC (1.66 and 4.10 tumors/mouse, respectively) at the two doses tested. Notably, blood and tissue analyses showed no signs of systemic toxicity for the p-XS-Asp fed group. In conclusion, p-XS-Asp, is less toxic and more effective chemopreventive agent than p-XSC and is a promising candidate to future clinical evaluation. Citation Format: Daniel Plano, Cesar Aliaga, Manoj K. Pandey, Arunangshu Das, Timothy K. Cooper, Shantu Amin, Arun K. Sharma. Pre-clinical chemopreventive efficacy of a novel hybrid p -XSC-aspirin compound in a NNK-induced A/J mouse lung cancer model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2139. doi:10.1158/1538-7445.AM2014-2139