Oridonin (Synonyms: NSC 250682)

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.