Oridonin is an inhibitor of protein kinase B (AKT; PKB), with IC50 values of 8.4 and 8.9μM for AKT1 and AKT2 respectively [1]. Oridonin preferentially blocks AKT kinase activity by inhibiting the phosphorylation of AKT substrates, thereby inhibiting downstream mTOR signaling [2]. Oridonin is also a high-affinity NLRP3 inflammasome inhibitor. Oridonin A can also inhibit NF-κB or MAPK activation [3].
In vitro, oridonin (1μM) treated breast cancer cell lines for three weeks, selectively inhibited the clonal growth of p-AKT High (MDAMB468, SKBR3 and HCC1569) cells but not p-AKT low (MDAMB231 and MCF- 10A) cells[2]. Incubation of A431 cells with oridonin (5, 20, 40 or 80 μM) resulted in a significant increase in cell death in a dose-dependent manner, inhibited total tyrosine kinase activity, and downregulated EGFR expression or EGFR phosphorylation [4]. Oridonin (5, 10, 20 μM) incubated OSCC cells dose-dependently led to cell apoptosis and induced cell cycle arrest in the G2/M phase [5].
In vivo, oral treatment of oridonin (160 mg/kg) in SCID mice transplanted with EG9 and HEG18 tumor cells significantly inhibited tumor growth without causing weight loss[1]. Oridonin (20 mg/kg), through intraperitoneal injection, significantly reduced the production of IL-1β in the joint tissue of wild-type C57BL/6 mice and alleviated acute joint swelling[3]. Intraperitoneal injection of oridonin (15 mg/kg) in xenograft mice inhibited the growth of colon cancer cells, significantly down-regulated the protein levels of GLUT1 and MCT1, inhibited glucose uptake and reduced lactate output, thereby inducing metabolic imbalance [6] .
References:
[1] Song M , Liu X , Liu K ,et al.Targeting AKT with oridonin inhibits growth of esophageal squamous cell carcinoma in vitro and patient derived xenografts in vivo[J].Molecular Cancer Therapeutics, 2018.
[2] Sun B, Wang G, Liu H, et al. Oridonin inhibits aberrant AKT activation in breast cancer[J]. Oncotarget, 2018, 9(35): 23878.
[3] He H, Jiang H, Chen Y, et al. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity[J]. Nature communications, 2018, 9(1): 2550.
[4] Li D , Wu L J , Tashiro S I , et al.Oridonin Inhibited the Tyrosine Kinase Activity and Induced Apoptosis in Human Epidermoid Carcinoma A431 Cells[J].Biological & Pharmaceutical Bulletin, 2007, 30(2):254-260.
[5] Wang H, Zhu L, Feng X, et al. Oridonin induces G2/M cell cycle arrest and apoptosis in human oral squamous cell carcinoma[J]. European Journal of Pharmacology, 2017, 815: 282-289.
[6]Yao Z, Xie F, Li M, et al. Oridonin induces autophagy via inhibition of glucose metabolism in p53-mutated colorectal cancer cells[J]. Cell death & disease, 2017, 8(2): e2633-e2633.
冬凌草甲素（Oridonin）是蛋白激酶B（AKT；PKB）的抑制剂，对 AKT1和 AKT2的 IC50 值分别为8.4和8.9μM[1]。冬凌草甲素通过抑制AKT底物的磷酸化优先阻断AKT激酶活性，从而抑制下游mTOR信号传导[2]。冬凌草甲素也是一种高亲和力NLRP3炎性体抑制剂，冬凌草甲素还可抑制NF-κB或MAPK激活[3]。
在体外，冬凌草甲素（1μM）处理乳腺癌细胞系三周，选择性抑制p-AKT High （MDAMB468，SKBR3和HCC1569）细胞的克隆生长，但不抑制p-AKT low （MDAMB231和MCF-10A）细胞[2]。冬凌草甲素（5, 20, 40 or 80μM）孵育A431细胞，剂量依赖性地导致细胞死亡率显著增加，抑制了总酪氨酸激酶活性，并下调EGFR表达或EGFR磷酸化[4]。冬凌草甲素（5, 10, 20μM）孵育OSCC细胞，剂量依赖性地导致细胞凋亡，诱导细胞周期停滞在G2/M期[5]。
在体内，冬凌草甲素（160mg/kg）口服治疗移植EG9和HEG18肿瘤细胞的SCID小鼠，显著抑制了肿瘤生长，且没有造成体重减轻[1]。冬凌草甲素（20mg/kg）通过腹腔注射，显著减少了野生型C57BL/6小鼠关节组织中IL-1β的产生，减轻了急性关节肿胀[3]。冬凌草甲素（15mg/kg）腹腔注射治疗异种移植小鼠，抑制结肠癌细胞的生长，显着下调GLUT1和MCT1的蛋白水平，抑制葡萄糖摄取并减少乳酸输出，从而诱导代谢失衡[6]。