Targeting AKT with Oridonin Inhibits Growth of Esophageal Squamous Cell Carcinoma In Vitro and Patient-Derived Xenografts In Vivo

• Published in: Molecular cancer therapeutics 2018-07, Vol.17 (7), p.1540-1553
• Main Authors: Song, Mengqiu, Liu, Xuejiao, Liu, Kangdong, Zhao, Ran, Huang, Hai, Shi, Yuanyuan, Zhang, Man, Zhou, Silei, Xie, Hua, Chen, Hanyong, Li, Yin, Zheng, Yan, Wu, Qiong, Liu, Fangfang, Li, Enmin, Bode, Ann M, Dong, Zigang, Lee, Mee-Hyun
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Activation; AKT protein; Animals; Anticancer properties; Antitumor activity; Apoptosis; Apoptosis - drug effects; Biomarkers; Cancer; Caspase; Caspase-3; Caspase-7; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cell survival; Chemotherapy; Cisplatin; Diterpenes, Kaurane - chemistry; Diterpenes, Kaurane - pharmacology; DNA microarrays; Enzyme inhibitors; Esophageal Squamous Cell Carcinoma - drug therapy; Esophageal Squamous Cell Carcinoma - genetics; Esophageal Squamous Cell Carcinoma - pathology; Esophagus; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Heterocyclic Compounds, 3-Ring - pharmacology; Histochemical analysis; Humans; Inflammation; Inhibitors; Isodon - chemistry; Kinases; Mice; Oncogene Protein v-akt - antagonists & inhibitors; Oncogene Protein v-akt - genetics; Patients; Pharmacology; Phosphorylation; Plant Extracts - pharmacology; Poly(ADP-ribose) polymerase; Signal Transduction - drug effects; Signaling; Solid tumors; Squamous cell carcinoma; Time dependence; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-17-0823

Overexpression or activation of AKT is very well known to control cell growth, survival, and gene expression in solid tumors. Oridonin, an inflammatory medical and diterpenoid compound isolated from , has exhibited various pharmacologic and physiologic properties, including antitumor, antibacterial, and anti-inflammatory effects. In this study, we demonstrated that oridonin is an inhibitor of AKT and suppresses proliferation of esophageal squamous cell carcinoma (ESCC) and The role of AKT in ESCC was studied using immuno-histochemical analysis of a tumor microarray, the effect of AKT knockdown on cell growth, and treatment of cells with MK-2206, an AKT inhibitor. Oridonin blocked AKT kinase activity and interacted with the ATP-binding pocket of AKT. It inhibited growth of KYSE70, KYSE410, and KYSE450 esophageal cancer cells in a time- and concentration-dependent manner. Oridonin induced arrest of cells in the G -M cell-cycle phase, stimulated apoptosis, and increased expression of apoptotic biomarkers, including cleaved PARP, caspase-3, caspase-7, and Bim in ESCC cell lines. Mechanistically, we found that oridonin diminished the phosphorylation and activation of AKT signaling. Furthermore, a combination of oridonin and 5-fluorouracil or cisplatin (clinical chemotherapeutic agents) enhanced the inhibition of ESCC cell growth. The effects of oridonin were verified in patient-derived xenograft tumors expressing high levels of AKT. In summary, our results indicate that oridonin acts as an AKT inhibitor to suppress the growth of ESCC by attenuating AKT signaling. .