Abstract 3930: Chemoprevention of metastatic colon cancer by a novel small molecule

Abstract

Abstract Introduction: Colon cancer is a one of the leading cause of death in both men and women. Metastatic colon cancer is responsible for mortality due to resistance to conventional therapies. Our group has previously reported that activation of AKT and Notch1 plays an important role in metastasis of colon cancer cells. As Notch1 and AKT regulates cell proliferation and are upstream of epithelial to mesenchymal transition (EMT) cascade, it seems interesting to explore their inhibition for pharmacological intervention. In the present study we identified a sesquiterpene molecule, Verrucarin J (VJ), that inhibited Notch1 expression and downregulated AKT mediated EMT transition in colon cancer cells. Methods: The anticancer effect of VJ was assessed on both colon cancer cells and stably AKT overexpressing colon cells by cell proliferation, apoptosis and Western blot analysis. For xenograft studies, pCMV/HCT-116 or AKT/HCT-116 cells (1.5 × 106) in a 50-μl final volume of phosphate-buffered saline (PBS) were injected subcutaneously into separate flanks of the mice. Also effects of VJ were determined in mouse model of colorectal cancer i.e. APC min+/_ mice. Statistical analysis was done by unpaired Student's t-test and one way ANOVA,*p≤0.05, **p≤0.01, ***p≤0.001. Results: Molecular analysis of VJ treatment on colon cancer cells revealed that it inhibited colon cancer growth by down regulating AKT and Notch1 signaling. Western blot analysis revealed that VJ inhibits AKT/NF-κβ/ Bcl2- signaling axis in colon cancer cells. VJ also Inhibited migration and invasion of colon cancer cells that corresponds with downregulation of mesenchymal marker expression. In addition, VJ treatment induces apoptosis in colon cancer cells as well as AKT overexpressing cells. Intraperitoneal administration of VJ in pCMV/HCT116 and AKT/HCT-116 xenograft mice revealed decrease in tumor volume in comparison with control mice. We also examined the in vivo efficacy of VJ in ApcMin/+ mouse model. Treatment of ApcMin/+ with VJ (0.5 mg/kg/IP/twice a week) over 12 weeks significantly reduced the number of intestinal polyps (distal 84%; Middle 63% and Proximal 2%) as compared vehicle treated mice. In addition, we also observed 50% reduction in number of colon tumors in VJ treated mice. Conclusion: In conclusion, our studies suggest that VJ inhibits both AKT and Notch1 signaling and induces apoptosis in colon cancer cells. In vivo studies revealed significant reduction in tumor formation in mice models of colon cancer. Hence VJ could be a viable therapeutic agent for treating patients with metastatic colon cancer. Citation Format: Deeksha Pal, Balaji Chandrasekaran, Ashish Tyagi, Becca Von Baby, Houda Alatassi, Murali Ankem, Chendil Damodaran. Chemoprevention of metastatic colon cancer by a novel small molecule [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 3930.