Chemopreventive efficacy of p-XSC is well documented but it failed due to systemic toxicity issues. This toxicity could partially be due to the release of poisonous hydrogen cyanide generated after p-XSC metabolizes to form active bis-selenol (p-XSeH). To address the said concern, we recently designed and developed p-XS-Asp, with the rationale that it would cleave in vivo to release the active p-XSeH and aspirin instead of undesired HCN, thus making the compound less toxic and possibly more potent than p-XSC. Indeed, we have shown previously that p-XS-Asp inhibits NNK-induced lung tumorigenesis in A/J mice more effectively than p-XSC in a complete A/J mouse model, and is better tolerable. The complete model, however, does not reveal at what stage of carcinogenesis does p-XS-Asp acts. In the current study, we evaluated the stage-specificity of chemopreventive efficacy of p-XS-Asp in NNK-induced lung carcinogenesis in A/J mice models. A/J mice were divided into 7 distinct groups (n=30 per group, half male, half female; except group 1 and 2 where n=10). The mice were fed AIN-93M diet (control) or p-XS-Asp diet until they reached termination end point of 26 weeks (adenomas) and 40 weeks (adenocarcinomas). Two weeks after the experiment started, all the groups, except for group 1 and 2, were given a single IP injection of 10 µmol (100 mg/kg) of NNK. Group 3 and 4 were on complete control AIN93M and p-XS-Asp diets, respectively. Group 5 (peri-initiation) was on p-XS-Asp for the first 3 weeks and then on the control diet till the end of the experiment. On the other hand, group 6 (post-initiation) was on control diet for 3 weeks and then was changed to the p-XS-Asp diet. In the progression group 7, mice were on control diet for 14 weeks and subsequently changed to p-XS-Asp diet. The Groups 4 and 5 mice showed a remarkable decrease in the tumor multiplicity (TM) and incidence (TI) as compared to the mice on control diet at both 26 and 40 week time-points. The TM in male mice for groups 1, 2, 3, 4, 5, 6 and 7 at 26 weeks was 0.6, 0, 5.7, 1, 1.54, 4.27, and 6.27, respectively, while at 40 weeks, it was 0.2, 0, 7.7, 1, 1.8, 4.1, and 4.9, respectively. A similar trend was also observed in female mice. These data clearly demonstrated that robust inhibition at peri-initiation stage is mainly responsible for the activity observed in the complete model. The inhibition of both O6-methylguanine and pyridoxobutyl mutagenic DNA adducts by p-XS-Asp further compliments that the compound acts at initial stages of carcinogenesis. Body weights comparison and the blood and tissue analyses showed no systemic toxicity for the p-XS-Asp fed groups. RNA-seq data of the tumor tissues showed numerous signaling pathways to be affected in p-XS-Asp treated mice. The exact mechanism of action is still under investigation. In summary, our results show that p-XS-Asp may be promising candidate for future clinical evaluation as a lung cancer preventive agent.

Citation Format: Asif Raza, Amandeep Singh, Cesar Aliaga, Daniel Plano, Shantu Amin, Arun K. Sharma. Stage-specific inhibition of NNK-induced lung carcinogenesis by 1,4-phenylenebis(methylene)seleno-aspirin (p-XS-Asp) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2596.