Abstract 2603: Discovery of chemopreventive agents from licorice (Glycyrrhiza Uralensis)

Traditional Chinese Medicine (TCM) provides a rich resource of potential chemoprevention agents; however, the complexity arise from its multi-components and multi-targets nature hindered in-depth investigations and translations. Licorice is one of the most commonly utilized TCM herbal medicine which possesses many pharmacological activities including cancer prevention. We isolated over 120 licorice-derived compounds and systemically screened these compounds using cellular and molecular models including cytotoxicity, nitric oxide production, NF-κB and ARE luciferase reporters, and other models. Isoangustone A (IAA) is an isoprenyled isoflavonoid which has been reported to induce apoptosis and cell cycle arrest in prostate cancer cells, and it was identified as a NF-κB inhibitor in our assays. IAA significantly inhibited NF-κB signaling in SW480 colorectal adenocarcinoma cells, and decreased the expression of Cox-2 and iNOS. Overexpression of constitutively activated IKKβ potently stimulated NF-κB signaling and reversed IAA-mediated inhibition. Oral administration of IAA significantly inhibited dextran sodium sulfate-induced NF-κB signaling and the expression of Cox-2 and iNOS in mouse colon tissue, and alleviated symptoms of colitis without observable acute toxicity. IAA and similar compounds also induced autophagy in various cancer cells, and inhibition of autophagy significant reversed IAA-induced cell death, suggesting the existence of autophagic cell death. IAA caused cleavage and aggregation of LC-3 accompanied with p62 degradation, and typical autophagic morphology was observed by transmission electronic microscopy. Overexpression of dominant negative AMPK or treatment with AMPK inhibitor demonstrated that activation of AMPK was important for IAA-induced autophagy, while inhibition of Akt was not. Further studies suggest that metabolic stresses is essential for the pharmacological activities of IAA, and primary molecular target were identified. Notably, IAA significantly inhibited tumor growth in nude mice xenograft model. These results suggest that IAA is potentially an anti-inflammatory bowel disease and anti- colorectal cancer agent. Based on the structural similarity, several other compounds were found to possess even stronger anti-inflammation, pro-apoptotic and autophagy-inducing activities. The present work discovered several promising chemopreventive compounds from licorice that deserve future study, and provides an example of study on TCM in chemoprevention. Several other compounds were identified as Nrf2/ARE signaling modulators or apoptosis/autophagy inducers and further investigated. The present works were supported by the National Natural Science Foundation of China (No. 81272468, 81472657). Citation Format: Shunan Tang, Shuai Ji, Yongrui Wang, Ye Min, Siwang Yu, Tony A-N. Kong. Discovery of chemopreventive agents from licorice (Glycyrrhiza Uralensis). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2603.