Abstract 4299: Targeting AKT with oridonin inhibits growth of esophageal squamous cell carcinoma in vitro and patient-derived xenografts in vivo

Esophageal cancer is the sixth leading cause of cancer death worldwide and has low survival rates with poor prognosis. Hyperactivation of AKT has been reported to modulate cell growth, survival, and gene expression in various solid tumors. Oridonin, an inflammatory medical and diterpenoid compound isolated from Rabdosia rubescens, has exhibited various pharmacologic and physiologic properties, including antitumor, antibacterial, and anti-inflammatory effects. In this study, we aimed to investigate the effects of oridonin on the proliferation and growth of ESCC and to elucidate its underlying mechanisms of action. We found that oridonin is an inhibitor of AKT and induces cell cycle arrest and apoptosis in ESCC cells and attenuates growth of patient derived xenograft (PDX) tumors in vivo by interfering with AKT signaling pathways through MTT assay, anchorage-independent cell growth assay and Cell cycle and apoptosis analyses. AKT was developed as a dierctly target of oridonin by in vitro kinase assay, ex vivo and in vitro pull-down assay and computational docking model. Mechanistically, oridonin diminished the phosphorylation and activation of AKT and supressed the downstream of p-GSK-3β, p-mTOR and NF-kB activity. Moreover, a combination of oridonin and 5-fluorouracil or cisplatin (clinical chemotherapeutic agents) enhanced the inhibition of ESCC cell growth. Overall, our study suggests that oridonin can inhibit progression of ESCC tumors in vitro and in vivo by suppressing AKT signaling through its direct targeting of AKT. Thus, this study might provide useful information in the clinical application of oridonin for ESCC chemotherapy.

Citation Format: Mengqiu Song, Ran Zhao, Hua Xie, Hanyong Chen, Kangdong Liu, Ann M. Bode, Mee-Hyun Lee, Zigang Dong. Targeting AKT with oridonin inhibits growth of esophageal squamous cell carcinoma in vitro and patient-derived xenografts in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4299.