Oridonin

Sichuan Da Xue Xue Bao Yi Xue Ban. 2014 Nov;45(6):903-7.

Anti-leukemia effect of oridonin on T-cell acute lymphoblastic leukemia[Pubmed: 25571712]

To investigate the antileukemia effect of Oridonin on T-cell acute lymphoblastic leukemia cell line CEM.
METHODS AND RESULTS:
Human T-cell acute lymphoblastic leukemia cell line CEM was cultured in vitro. The 50% inhibition concentration (IC50) of Oridonin against CEM cells was examined using modified MTT assay. The cellular morphologic changes were observed using a light microscope. The percent of apoptosis of CEM cells after drug treatment was evaluated by flow cytometric analysis. The active levels of AKT/mTOR, RAF/MEK/ ERK, STAT5 signaling pathways and the expression levels of Bcl-2 and BAX were examined by Western blot. Oridonin inhibited the growth of CEM cells in time- and dose dependent manner and the ICs0 of Oridonin was (7. 37± 1. 99) μmol/L after 72 h treatment. The cellular membrane of CEM cells treated with Oridonin became unsharp, some of them disintegrated. Oridonin induced apoptosis in CEM cells and the percent of apoptosis rate after 0, 5, 7.5, 10 μmol/L Oridonin treatment for 24 h were (4. 8±2. 11)%, (19.03±12.54)% ,(40.27± 3.31) / and (57. 23 ± 6. 69)% respectively. Oridonin inhibited activation of mTOR, P70S6, 4EBP1, RAF. ERK and STAT5 signaling protein, which were constitutively activated in CEM cells, however, Oridonin had no inhibitory effect on AKT kinase. Oridonin down-regulated the level of anti apoptotic protein Bcl-2 and up-regulated the expression of pro-apoptotic protein Bax.
CONCLUSIONS:
Oridonin exerted antileukemia effect in CEM cells by inhibiting the activation of mTOR/P70/4EBP1, RAF/ERK and STATS signaling pathways, down-regulating the expression of Bel-2 and up-regulating the expression of BAX.

Zhong Yao Cai. 2014 Jul;37(7):1230-3.

Experimental study on anti-pancreatic cancer effect of oridonin.[Pubmed: 25566662]

To investigate the apoptotic effect of Oridonin in human pancreatic cancer cells PANC-1, and to explore the underlying mechanism.
METHODS AND RESULTS:
MTT assay was used to measure the cell viability. Apoptosis was determined by confocal laser scanning microscope after Hoechst 33342 staining and flow cytometry analysis after PI staining. The regulation of JNK and p38 MAPK signaling pathway proteins was examined by Western blot analysis. Treatment with Oridonin for 24 h resulted in a marked decrease in cell viability in a dose-dependent manner. The IC50 value was determined as 49.80 μmol/L for 24 h. After treatment with 50 micromol/L and 80 μmol/L Oridonin for 24 h, typical apoptotic nucleus alterations were observed with confocal laser scanning microscope and apoptotic rates of PANC-1 cells increased by flow cytometry analysis. Treatment with 80 μmol/L Oridonin down-regulated protein expression of JNK, p38 and increased the expression of p-JNK, p-p38. Furthermore, 80 μmol/L Oridonin treatment decreased the expression of down-stream proteins Caspase-9, Caspase-3 and PARP in the apoptotic pathway as well as activated the cleavage of Caspase-9.
CONCLUSIONS:
Oridonin can induce apoptosis of PANC-1 cells through JNK and p38 MAPK pathway proteins.

Mol Cancer Ther . 2018 Jul;17(7):1540-1553.

Targeting AKT with Oridonin Inhibits Growth of Esophageal Squamous Cell Carcinoma In Vitro and Patient-Derived Xenografts In Vivo[Pubmed: 29695636]

Abstract 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.

Cell Mol Biol (Noisy-le-grand). 2014 Dec 30;60(6):29-36.

Oridonin inhibits tumor growth in glioma by inducing cell cycle arrest and apoptosis.[Pubmed: 25553351]

Glioma is the most common malignant intracranial tumors. Despite newly developed therapies, these treatments mainly target oncogenic signals, and unfortunately, fail to provide enough survival benefit in both human patients and mouse xenograft models, especially the first-generation therapies. Oridonin is purified from the Chinese herb Rabdosia rubescens and considered to exert extensive anti-cancer effects on human tumorigenesis.
METHODS AND RESULTS:
In this study, we systemically investigated the role of Oridonin in tumor growth and the underlying mechanisms in human glioma. We found that Oridonin inhibited cell proliferations in a dose- and time-dependent manner in both glioma U87 and U251 cells. Moreover, these anti-cancer effects were also confirmed in a mouse model bearing glioma. Furthermore, cell cycle arrest in S phase was observed in Oridonin-mediated growth inhibition by flow cytometry. Cell cycle arrest in S phase led to eventual cell apoptosis, as revealed by Hoechst 33342 staining and annexin V/PI double-staining. The cell apoptosis might be accomplished through a mitochondrial manner.
CONCLUSIONS:
In all, we were the first to our knowledge to report that Oridonin could exert anti-cancer effects on tumor growth in human glioma by inducing cell cycle arrest and eventual cell apoptosis. The identification of Oridonin as a critical mediator of glioma growth may potentiate Oridonin as a novel therapeutic strategies in glioma treatments.

Acta Biochim Biophys Sin (Shanghai). 2015 Mar;47(3):164-73.

Oridonin inhibits BxPC-3 cell growth through cell apoptosis.[Pubmed: 25651847]

Oridonin, an ent-kaurene diterpenoid extracted from the traditional Chinese herb Rabdosia rubescens, has multiple biological and pharmaceutical functions and has been used clinically for many years. While the antitumor function of Oridonin has been corroborated by numerous lines of evidence, its anticancer mechanism has not been well documented.
METHODS AND RESULTS:
In this study, the pancreatic cancer cell line BxPC-3 was used as a model to investigate a possible anticancer mechanism of Oridonin through examining its effects on cell viability. The results showed that Oridonin affected cell viability in a time- and dose-dependent manner. After exposure to different Oridonin concentrations, growth rates and cell cycle arrest of BxPC-3 cells were significantly reduced compared with untreated cells, suggesting its effects on proliferation inhibition. Detailed signaling pathway analysis by western blot analysis revealed that low-dose Oridonin treatment inhibited BxPC-3 cell proliferation by up-regulating p53 and down-regulating cyclin-dependent kinase 1 (CDK1), which led to cell cycle arrest in the G2/M phase. A high-dose Oridonin not only arrested BxPC-3 cells in the G2/M phase but also induced cell accumulation in the S phase, presumably through γH2AX up-regulation and DNA damage.
CONCLUSIONS:
In addition, our results showed that a cell subpopulation was stained with propidium iodide after Oridonin treatment. Protein quantification showed that cleaved poly(ADP-ribose) polymerase (PARP) expression was increased after a high-dose Oridonin treatment, especially after long-term exposure. Accompanied by the increased level of deactivated PARP in BxPC-3 cells, the apoptosis initiators caspase-3 and caspase-7 expressions were also significantly increased, suggesting that caspase-mediated apoptosis contributed to cell death.