Abstract 274: Selective chemopreventive efficacy of 1,4-phenylenebis(methylene)seleno-aspirin (p-XS-Asp) towards lung cancer
Authors: Plano Daniel , Ramisetti Srinivasa , Kim Sang-Yub , Pandey Manoj , Aliaga Cesar , Karelia Deepkamal N. , Berg Arthur , Sanmartin Carmen , Lu Junxuan , Amin Shantu , Sharma Arun K. 
Published: August 2018

1,4-Phenylenebis(methylene)selenocyanate (p-XSC) has been shown to inhibit tobacco carcinogen NNK induced lung tumor development in several animal models. This had placed p-XSC on the National Cancer Institute´s (NCI) list of chemopreventive agents for clinical development, but there were systemic toxicity issues. p-XSC metabolizes through the formation of active bis-selenol (p-XSeH) along with the release of poisonous hydrogen cyanide (HCN). We recently developed p-XS-Asp, with a rationale that it would cleave in vivo to release the active p-XSeH and aspirin, thus making the compound less toxic and possibly more potent than p-XSC. Indeed, we previously presented (AACR Annual Meeting 2014) that p-XS-Asp inhibited NNK-induced lung tumorigenesis in A/J mice more effectively than p-XSC, and was also more tolerable. At doses of 15 ppm and 7.5 ppm Se, p-XS-Asp showed a significantly marked decrease in the percentage of lung cancer incidence in vivo with only 50% and 87% of tumor incidence, as compared to p-XSC (79% and 100%), respectively. NNK-control showed an 100% tumor incidence. Likewise, the tumor multiplicity for p-XS-Asp group was 0.87 and 1.93 tumors/mouse as compared to the NNK-control (11.53) and p-XSC (1.66 and 4.10 tumors/mouse, respectively) at the two doses tested. Notably, blood chemistry and tissue analyses did not show systemic toxicity for the p-XS-Asp fed group.

We have now evaluated the underlying mechanisms of lung cancer preventive action of p-XS-Asp and its efficacy for inhibiting azoxymethane (AOM)- and dimethyl hydrazine (DMH)-induced Aberrant Crypt Foci (ACF) in Fischer F344 rats. At a dose of 7.5 ppm Se, p-XS-Asp was able to restore the expression of several genes (MMP9, COX-2, Myc, SphK1 and RELA), that were over-expressed in the NNK group, to control or even lower levels. The AKT1 gene expression was much lower in the lung tissue of p-XS-Asp treated mice at this dose compared to both negative and NNK control groups. Therefore, p-XS-Asp might be exerting its chemopreventive effect on NNK-induce lung tumorigenesis via inhibiting COX-2 mediated PI3K/Akt signaling pathway.

Interestingly, contrary to the striking inhibition of lung tumorigenesis, p-XS-Asp failed to significantly inhibit AOM- or DMH-induced formation of ACF in Fischer F344 rats. In both AOM and DMH models, aspirin (positive control) significantly reduced the number of ACF and large ACF per area (cm2) by 37.4% and 33.8%, respectively. On the other hand, both p-XSC and p-XS-Asp showed no significant inhibitory effect on the formation of ACF and large ACF. Taken together, our results have shown p-XS-Asp to selectively prevent the lung, but not colon, tumorigenesis, and thus is a promising candidate for further development as a lung cancer preventive agent.

Citation Format: Daniel Plano, Srinivasa Ramisetti, Sang-Yub Kim, Manoj Pandey, Cesar Aliaga, Deepkamal N. Karelia, Arthur Berg, Carmen Sanmartin, Junxuan Lu, Shantu Amin, Arun K. Sharma. Selective chemopreventive efficacy of 1,4-phenylenebis(methylene)seleno-aspirin (p-XS-Asp) towards lung cancer [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 274.