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 Rabdosia rubescens, 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) in vitro and in vivo. 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 G2–M cell-cycle phase, stimulated apoptosis, and increased expression of apoptotic biomarkers, including cleaved PARP, caspase-3, caspase-7, and Bims 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. Mol Cancer Ther; 17(7); 1540–53. ©2018 AACR.

中文翻译：

---

用冬凌草素靶向 AKT 可抑制体外食管鳞状细胞癌和体内患者来源的异种移植物的生长

众所周知，AKT 的过度表达或激活可控制实体瘤中的细胞生长、存活和基因表达。Oridonin 是一种从 Rabdosia rubescens 中分离出来的炎症药物和二萜类化合物，具有多种药理和生理特性，包括抗肿瘤、抗菌和抗炎作用。在这项研究中，我们证明了冬凌草甲苷是 AKT 的抑制剂，并在体外和体内抑制食管鳞状细胞癌 (ESCC) 的增殖。使用肿瘤微阵列的免疫组织化学分析、AKT 敲低对细胞生长的影响以及用 AKT 抑制剂 MK-2206 处理细胞，研究了 AKT 在 ESCC 中的作用。Oridonin 阻断 AKT 激酶活性并与 AKT 的 ATP 结合口袋相互作用。它抑制了 KYSE70、KYSE410、和 KYSE450 食管癌细胞以时间和浓度依赖性方式。Oridonin 诱导细胞在 G2-M 细胞周期阶段停滞，刺激细胞凋亡，并增加凋亡生物标志物的表达，包括 ESCC 细胞系中裂解的 PARP、caspase-3、caspase-7 和 Bims。从机制上讲，我们发现冬凌草素减少了 AKT 信号的磷酸化和激活。此外，冬虫夏草素和 5-氟尿嘧啶或顺铂（临床化学治疗剂）的组合增强了对 ESCC 细胞生长的抑制。在表达高水平 AKT 的患者来源的异种移植肿瘤中证实了冬凌草甲苷的作用。总之，我们的结果表明冬凌草甲素作为 AKT 抑制剂通过减弱 AKT 信号来抑制 ESCC 的生长。摩尔癌症治疗; 17(7); 1540-53。©2018 AACR。