Abstract 2794: A novel bis-aspirinyl selenazolidine compound AS-10 as potential colon cancer therapeutic
Authors: Karelia Deepkamal N. , Pandey Manoj , Plano Daniel , Amin Shantu , Sharma Arun K. 
Published: August 2018

Despite rigorous screening and aggressive surgical and chemotherapeutic treatments, colorectal cancer (CRC) remains the third leading cause of cancer-related deaths in women and the second leading cause in men in the United States. It is expected to cause about 50,260 deaths during 2017 (American Cancer Society). The 5-year survival rate for patients with colorectal cancer (CRC) is 64%, although for patients who present with distant metastases at diagnosis the 5 year survival is only 12%. Therefore, there is an urgent need to develop effective therapeutic strategies that will enhance the survival and improve quality of life of CRC patients. Non-steroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, have recently been shown to be effective in reducing colon cancer incidences and are proposed to be effective CRC chemopreventive agents. Through extensive structure activity relationship (SAR) studies based on designing selenium-NSAID hybrid small molecules, we have identified a small drug-like molecule, AS-10, which contains two aspirinyl groups flanked to a selenazolidine ring. AS-10 effectively inhibited the viability of CRC cells (HT29, RKO, and HCT116) with an EC50 in the range of 1 to 2.5 µM. Interestingly, AS-10 showed more selectivity towards killing cancer cells than normal mouse embryonic fibroblasts (MEFs) and was &gt;50 times more potent than current standard of care, 5-FU, for in killing CRC cells. Cell cycle studies revealed AS-10 treated CRC cells to have G1 and G2/M phase cell cycle arrest. Further, increasing protein expression of cell cycle inhibitory protein p21 confirmed our cell cycle findings in AS-10 treated CRC cells. Since these CRC cell lines are p53 mutant cells, it was noteworthy to see p53 independent expression of p21. Moreover, we explored the possibility of apoptosis in these cell cycle arrested cells and found that AS-10 treatment increased casapse 3/7 activity, and cells positive for phosphatidylserine on the outer cell membrane surface indicative of apoptosis. In silico evaluation shows that AS-10 with cLogP 2.2 and MW 473 fits perfectly into the requirements of Lipinski's Rule-of-Five, formulated to determine the drug-likeness of a small molecule. In addition, in nude mice, AS-10 exhibited a high maximum tolerated dose (MTD) (~80 mg/kg, IP, three times per week). Furthermore, AS-10 (45 mg/kg, IP, three times per week) effectively inhibited tumor growth by ~70% in a nude mouse colon cancer xenograft model without any apparent systemic toxicity. Overall, AS-10 appears to be a promising small molecule worthy of further development as a therapeutic for CRC patients.

Citation Format: Deepkamal N. Karelia, Manoj Pandey, Daniel Plano, Shantu Amin, Arun K. Sharma. A novel bis-aspirinyl selenazolidine compound AS-10 as potential colon cancer therapeutic [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 2794.