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Oridonin



RESEARCH


Recent Advances in the Molecular Basis of Anti-Neoplastic Mechanisms of Oridonin
Source:
Tian W, Shen S-y. Chin J Integr Med 2013 Apr;19(4):315-320

Rabdosia rubescens has a long history of use in China. Between the 1970s and 1990s, many researchers in the Henan province of China tried to use the herb in esophageal and gastric cardia neoplasm treatment. They found that use of its entire plant purportedly showed evidence of efficacy.[1]
Oridonin, a diterpenoid isolated from Rabdosia rubescens, has been proven to possess various pharmacological and physiological effects such as anti-inflammation, anti-bacterial, and anti-neoplastic, although in recent years, more attention has been paid to its anti-neoplastic effects. For example, oridonin can trigger cell cycle arrest, apoptosis, and autophagy in different neoplastic cell lines.[2,3] In 1976, the relationship between anti-neoplastic activity and the chemical structure of oridonin was first demonstrated. [4]
A report demonstrated that oridonin might cooperate with all trans-retinoic acid (ATRA) to induce differentiation of APL cells. [5] This finding suggests that oridonin is a potential candidate for acute promyelocytic leukemia cancer therapy.
Another investigation revealed that secretion of interleukin-2 (IL-2), interferon-?, interleukin-12 p40, and tumor necrosis factor-? in murine splenic lymphocytes can be inhibited through decreasing cytokine mRNA expression levels when treated with oridonin. In addition, IL-2 levels in the blood serum of experimental animals treated with oridonin were significantly decreased in a dose-dependent manner. [6]
References:
1. Fan QX, Li XY, Wang RL, Fan KS, Gao GQ, Chen HM, et al. Treatment with oridonin in 287 patients with esophageal and gastric cardia neoplasm. Chin J Surgery Integr Tradit (Chin) 1997;3:380-381.
2. Han QB, Li ML, Li SH, Mou YK, Lin ZW, Sun HD. Entkaurane diterpenoids from Isodon rubescens var. lushanensis. Chem Pharm Bull 2003;51:790-793.
3. Ikezoe T, Chen SS, Tong XJ, Heber D, Taquchi, Koeffler HP. Oridonin induces growth inhibition and apoptosis of a variety of human cancer cells. Int J Oncol 2003;23:1187-1189.
4. Fujita E, Nagao Y, Node M, Kaneko K, Nakazawa S, Kuroda H. Antitumor activity of the isodon diterpenoids: structural requirements for the activity. Cell Mol Life Sci 1976;32:203-206
5. Gao F, Tang Q, Yang P, Fang Y, Li W, Wu Y. Apoptosis inducing and differentiation enhancement effect of oridonin on the all-trans-retinoic acid-sensitive and -resistant acute promyelocytic leukemia cells. Int J Lab Hematol 2010;32:e114-122
6. Liu J, Yang F, Zhang Y, Li J. Studies on the cell-immunosuppressive mechanism of Oridonin from Isodon serra. Int Immunopharmacol 2007;7:945-954

Oridonin induces apoptosis, inhibits migration and invasion on highly-metastatic human breast cancer cells.

Wang S, Zhong Z, Wan J, et al. Am J Chin Med. 2013;41(1):177-96. doi: 10.1142/S0192415X13500134.
Oridonin, a natural tetracycline diterpenoid isolated from Chinese herb Rabdosia rubescens, has been reported to be a potent cytotoxic agent against a wide variety of tumors. However, its effect on highly metastatic breast cancer cells has not been addressed. In this study, we investigated the effects of oridonin on growth, migration and invasion of highly-metastatic human breast cancer cells. Our results showed that oridonin induced potent growth inhibition on human breast cancer cells MCF-7 and MDA-MB-231 in a time- and dose-dependent manner. According to the flow cytometric analysis, oridonin suppressed MCF-7 cell growth by cell cycle arrest at the G2/M phase and caused accumulation of MDA-MB-231 cells in the Sub-G1 phase. The induced apoptotic effect of oridonin was further confirmed by a morphologic characteristics assay and TUNEL assay. Oridonin triggered the reduction of Bcl-2/Bax ratio, caspase-8, NF-κB (p65), IKKα, IKKβ, phospho-mTOR, and increased expression level of cleaved PARP, Fas and PPARγ in a time-dependent manner. Immunofluorescent analysis showed that γH2AX-containing nuclear foci were significant in oridonin-treated MDA-MB-231 cells. Meanwhile, oridonin significantly suppressed MDA-MB-231 cell migration and invasion, decreased MMP-2/MMP-9 activation and inhibited the expression of Integrin β1 and FAK.
In conclusion, oridonin inhibited the growth and induced apoptosis in breast cancer cells, which might be related to DNA damage and activation of intrinsic or extrinsic apoptotic pathways. Moreover, oridonin also inhibited tumor invasion and metastasis in vitro possibly via decreasing the expression of MMPs and regulating the Integrin β1/FAK pathway in MDA-MB-231 cells.

Oridonin induces apoptosis in gastric cancer through Apaf-1, cytochrome c and caspase-3 signaling pathway.
Sun KW, Ma YY, Guan TP, et al. World J Gastroenterol. 2012 Dec 28;18(48):7166-74. doi: 10.3748/wjg.v18.i48.7166.
AIM:
To investigate the effect and mechanism of oridonin on the gastric cancer cell line HGC-27 in vitro.
METHODS:
The inhibitory effect of oridonin on HGC-27 cells was detected using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. After treatment with 10 μg/mL oridonin for 24 h and 48 h, the cells were stained with acridine orange/ethidium bromide. The morphologic changes were observed under an inverted fluorescence microscope. DNA fragmentation (a hallmark of apoptosis) and lactate dehydrogenase activity were examined using DNA ladder assay and lactate dehydrogenase-release assay. After treated with oridonin (0, 1.25, 2.5, 5 and 10 μg/mL), HGC-27 cells were collected for anexin V-phycoerythrin and 7-amino-actinomycin D double staining and tested by flow cytometric analysis, and oridonin- induced apoptosis in HGC-27 cells was detected. After treatment with oridonin for 24 h, the effects of oridonin on expression of Apaf-1, Bcl-2, Bax, caspase-3 and cytochrome c were also analyzed using reverse-transcript polymerase chain reaction (RT-PCR) and Western blotting.
RESULTS:
Oridonin significantly inhibited the proliferation of HGC-27 cells in a dose- and time-dependent manner. The inhibition rates of HGC-27 treated with four different concentrations of oridonin for 24 h (1.25, 2.5, 5 and 10 μg/mL) were 1.78% ± 0.36%, 4.96% ± 1.59%, 10.35% ± 2.76% and 41.6% ± 4.29%, respectively, which showed a significant difference (P < 0.05). The inhibition rates of HGC-27 treated with oridonin at the four concentrations for 48 h were 14.77% ± 4.21%, 21.57% ± 3.75%, 30.31% ± 4.91% and 61.19% ± 5.81%, with a significant difference (P < 0.05). The inhibition rates of HGC-27 treated with oridonin for 72 h at the four concentrations were 25.77% ± 4.85%, 31.86% ± 3.86%, 48.30% ± 4.16% and 81.80% ± 6.72%, with a significant difference (P < 0.05). Cells treated with oridonin showed typical apoptotic features with acridine orange/ethidium bromide staining. After treatment with oridonin, the cells became round, shrank, and developed small buds around the nuclear membrane while forming apoptotic bodies. Lactate dehydrogenase (LDH) release assay showed that after treated with 1.25 μg/mL and 20 μg/mL oridonin for 24 h, LDH release of HGC-27 caused by apoptosis increased from 22.94% ± 3.8% to 52.68% ± 2.4% (P < 0.001). However, the change in the release of LDH caused by necrosis was insignificant, suggesting that the major cause of oridonin-induced HGC-27 cell death was apoptosis. Flow cytometric analysis also revealed that oridonin induced significant apoptosis compared with the controls (P < 0.05). And the apoptosis rates of HGC-27 induced by the four different concentrations of oridonin were 5.3% ± 1.02%, 12.8% ± 2.53%, 28.5% ± 4.23% and 49.6% ± 3.76%, which were in a dose-dependent manner (P < 0.05). After treatment for 24 h, DNA ladder showed that oridonin induced a significant increase in DNA fragmentation in a dose-dependent manner. RT-PCR revealed that mRNA expression levels were up-regulated compared with the controls in caspase-3 (0.917 ± 0.103 vs 0.357 ± 0.019, P < 0.05), cytochrome c (1.429 ± 0.111 vs 1.002 ± 0.014, P < 0.05), Apaf-1 (0.688 ± 0.101 vs 0.242 ± 0.037, P < 0.05) and Bax (0.856 ± 0.101 vs 0.278 ± 0.027, P < 0.05) (P < 0.05), whereas down-regulated in Bcl-2 (0.085 ± 0.012 vs 0.175 ± 0.030, P < 0.05). Western blotting analysis also confirmed this result.
CONCLUSION:
Apoptosis of HGC-27 induced by oridonin may be associated with differential expression of Apaf-1, caspase-3 and cytochrome c, which are highly dependent upon the mitochondrial pathway.

Oridonin: targeting programmed cell death pathways as an anti-tumour agent.
Liu Z, Ouyang L, Peng H, Zhang WZ. Cell Prolif. 2012 Dec;45(6):499-507. doi: 10.1111/j.1365-2184.2012.00849.x.
Oridonin, an active diterpenoid isolated from traditional Chinese herbal medicine, has drawn rising attention for its remarkable apoptosis- and autophagy-inducing activity and relevant molecular mechanisms in cancer therapy. Apoptosis is a well known type of cell death, whereas autophagy can play either pro-survival or pro-death roles in cancer cells. Accumulating evidence has recently revealed relationships between apoptosis and autophagy induced by oridonin; however, molecular mechanisms behind them remain to be discovered.
In this review, we focus on highlighting updated research on oridonin-induced cell death signalling pathways implicated in apoptosis and autophagy, in many types of cancer. In addition, we further discuss cross-talk between apoptosis and autophagy induced by oridonin, in cancer. Taken together, these findings open new perspectives for further exploring oridonin as a potential anti-tumour agent targeting apoptosis and autophagy, in future anti-cancer therapeutics.

Oridonin, a diterpenoid extracted from medicinal herbs, targetsAML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo
The Isodon plant, Rabdosia rubescens (RR), and its extracts, were shown in China to be able to suppress disease progress, reduce tumor burden, alleviate syndrome, and prolong survival in patients with esophageal, gastric carcinoma or liver cancer.1-5 Of interest, other Isodon plants including Isodon japonicus Hara (IJ) and I trichocarpus (IT) were also applied as home remedies for similar disorders in Japan and Korea.6 Oridonin a bitter tetracycline diterpenoid compound, was isolated from RR, IJ, and IT separately,7,8 suggesting oridonin should be an essential antitumor component of Isodon plants. Studies showed that oridonin induced apoptosis in a variety of cancer cells including those from prostate, breast, non–small cell lung cancers, acute leukemia (NB4, HL-60 cells), glioblastoma multiforme, and human melanoma cells.9-12 Oridonin could also increase lifespan of mice bearing Ehrlich ascites or P388 lymphocytic leukemia.13,14

Oridonin triggered apoptosis in more than 50% of t(8;21) leukemic cells in vitro at concentration of 2 M or higher accompanied by degradation of AE oncoprotein, and showed significant antileukemia efficacies with low adverse effects in vivo. These data suggest possible beneficial effects for patients with t(8;21) acute myeloid leukemia (AML).

Source:
Zhou G-B, Kang H, Wang L, et al. Oridonin, a diterpenoid extracted from medicinal herbs, targetsAML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo. BLOOD, 15 APRIL 2007  VOLUME 109, NUMBER 8

References:
1. Henan Robdosia Coop Group. Efficacy of Rabdosia rubescens in treating 101 patients with esophageal or gastric cardiac carcinoma. J Henan Med Coll. 1980;5:31-37.
2. Tang W, Eisenbrand G. Chinese Drugs of Plant Origin: Chemistry, Pharmacology, and Use in Traditional and Modern Medicine. Berlin, Germany: Springer-Verlag; 1992.
3. Wang R, Fan K, Fan Q, et al. Clinical observation of 437 cases with esophageal cancer. Zhongguo Zhong Xi Yi Jie He Za Zhi. 1989;9:740-741.
4. Wang R, Wang L. Efficacy of Rabdosia rubescens in treating 95 cases with esophageal and gastric cardiac cancer. Cancer Res Prev Treatment. 1994;11:86-87.
5. Wang R, Gao B, Xiong M, et al. Studies on synergistic effect of Rabdosia Rubescens and chemotherapy on esophageal cancer. Chin J Oncol. 1986;8:297-298.
6. Fujita T, Takeda Y, Sun HD, et al. Cytotoxic and antitumor activities of Rabdosia diterpenoids. Planta Med. 1988;54:414-417.
7. Fujita E, Fujita T, Katayama H, Shibuya M. Terpenoids, part XV: structure and absolute configuration of oridonin isolated from Isodon japonicus trichocarpus. J Chem Soc (C). 1970;21:1674- 1681.
8. Henan Medical Institute, Henan Medical College, Yunnan Institute of Botany. Oridonin: a new antitumor subject. Chin Sci Bull. 1978;23:53-56.
9. Li XT, Lin C, Li PY, Zhang TM. Comparative study on the sensitivities of seven human cancer cell lines to rubescensine A. Acta Pharmaceutica Sinica. 1985;20:243-246.
10. Zhang CL, Wu LJ, Zuo HJ, et al. Cytochrome c release from oridonin-treated apoptotic A375-S2 cells is dependent on p53 and extracellular signal- regulated kinase activation. J Pharmacol Sci. 2004;96:155-163.
11. Ikezoe T, Chen SS, Tong XJ, et al. Oridonin induces growth inhibition and apoptosis of a variety of human cancer cells. Int J Oncol. 2003;23:1187- 1193.
12. Chen S, Gao J, Halicka HD, et al. The cytostatic and cytotoxic effects of oridonin (Rubescenin), a diterpenoid from Rabdosia rubescens, on tumor cells of different lineage. Int J Oncol. 2005;26: 579-588.

 
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