Title: Abstract 4514: ASR458, a small molecule, targets Notch1 signaling in advanced colorectal cancer
Abstract: Abstract Cancer-related mortality rates are amongst the highest in colorectal cancer (CRC). Previously we have reported that Withaferin A (WA), a natural compound, induces apoptosis and inhibits AKT mediated pro-survival signaling resulting in growth inhibition both in vitro and in vivo models of colon cancer. Owing to the encouraging results with WA, we have developed a series of acetylated pro-drug conjugates of WA and our initial structure-activity relationship (SAR) studies led to the identification of a novel small molecule ASR-458 as the lead compound. Interestingly, ASR-458 has demonstrated better efficacy by inhibiting colon cancer cell growth at nano-molar concentration, even in AKT overexpressing (AKT/HCT) HCT-116 cells (IC50: 750nm). Induction of apoptosis was seen in both control vector and AKT overexpressed colon cancer cell lines. Induction of caspase mediated signaling confirmed the pro-apoptotic function of ASR-458 in colon cancer cells. Inhibition of pAKT (ser473) resulted in downregulation of Notch1 downstream signaling pathways (Presenilin 1, NFkB activation and BCl-2 expression) in AKT/HCT colon cancer cells. Epithelial to mesenchymal transition (EMT) is a major hallmark of metastatic colon cancer. ASR-458 also downregulated the expression of EMT markers snail as well as β-Catenin and significantly impaired invasive as well as the migratory efficiency of AKT/HCT cells. Our ongoing xenograft studies will validate the in vivo efficacy of ASR-458 (1mg/kg/BW by IP weekly 2 times for six weeks) will confirm the chemotherapeutic effect of the compound against colon cancer cells. Overall these results emphasize ASR-458 to be a promising small molecule as compared to WA. ASR-458 targets both AKT and Notch1 signaling pathways which remains an important target for the development of effective treatment of metastatic stage of CRC. Citation Format: Balaji Chandrasekaran, Deeksha Pal, Ashish Tyagi, Srinivasa R Ramisetti, Arun K Sharma, Murali Ankem, chendil Damodaran. ASR458, a small molecule, targets Notch1 signaling in advanced colorectal 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 4514.
Publication Year: 2018
Publication Date: 2018-07-01
Language: en
Type: article
Indexed In: ['crossref']
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