Abstract 4501: Development of novel Lithocholic acid carboxamides with antiproliferative and pro-apoptotic effects on human cancer cells

Abstract

Abstract Bile acids, the products of cholesterol catabolism, are synthesized in the liver and subsequently excreted into the bile canaliculus and the digestive tract as N-acyl conjugates of glycine or taurine. Among all bile acids, Lithocholic acid (LCA) and Ursodeoxycholic acid (UDCA) conjugates have been reported to inhibit the growth of various human cancer cells both in vitro and in vivo. Most importantly LCA has been shown to inhibit growth of different cancer cell lines including prostate and neuroblastoma cells, while sparing normal cells. In addition, a report has shown LCA-amphiphiles to be effective anti-tumor agents in a colon cancer xenograft model. In contrast, there are reports indicating that LCA may promote dimethyl hydrazine (DMH) induced colon carcinogenesis and may also act as a carcinogen itself. This indicates that in spite of having anti-cancer properties, LCA may pose a risk of developing colon cancer. We hypothesized that LCA structure can be optimized to eliminate the carcinogenesis promoting properties, while enhancing its potency to create effective therapeutics against colon, prostate, and other cancers. Therefore, we designed and synthesized a series of novel cyclic and acyclic LCA-carboxamides by blocking the acid functionality of LCA. The cytotoxicity of the novel analogs was evaluated against colon (HT29) and prostate (DU145) cancer cells. Three analogs ASR-320, ASR-322 and ASR-339 inhibited the viability of these cells with an EC50 value of 5-10 μM, while LCA had no effect on cell viability at highest dose used (50 μM). The results suggests that the new analogs are at least 10 times more potent than the parent compound, LCA. One of the agents, induced apoptosis in both prostate (DU145) and colon (HT29) cancer cell lines, as indicated by Caspase 3 activation and PARP degradation. Currently, we are further optimizing the structure based on the initial leads and investigating efficacy and mechanistic studies in prostate and colon cancer models. Detailed results of these investigations will be presented. Citation Format: Srinivasa R. Ramisetti, Deepkamal Karelia, Melanie Neagley, Shantu Amin, Arun K. Sharma. Development of novel Lithocholic acid carboxamides with antiproliferative and pro-apoptotic effects on human cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4501. doi:10.1158/1538-7445.AM2015-4501