General

Scientific Names: Rabdosia rubescens (Hamsl.) Hara

Common Names: Dong Ling Cao, Bing Ling Cao, Yan Ming Cao, Cai Hua Cao.

BOTANICAL:

植物特征： 冬凌草在冬季早晨，气温降至℃以下时，其内含物与地面水蒸气在茎上凝结成如纸的冰片，卷曲成各种图案，远看像花絮一样，素雅可观，我国药植物学家为了确切地表示它的这一特点，故名冰凌草。属唇形科香茶菜属，多年生草本或亚灌木植物，高３０－１００厘米，基部呈圆柱形，上部四棱形，分梗发达，密被绒毛，叶菱状或卵圆形互生，正面有柔毛、腺点，叶背有白色短绒毛，叶缘锯齿，聚伞花序，３－５朵花在茎和分枝上排成狭长圆锥花序，花萼钟形，萼齿呈２／３式二唇形，花冠淡蓝或紫红色，雄蕊及花柱伸出，小坚果倒卵状三棱形，褐色，无毛。它以地上部全株入药，而以叶的药效最佳。

Pharmacology

化学成分: 冬凌草主要内含物为冬凌草甲素、乙素、丙素和丁素，还含有挥发油生物碱、苦味成分、内脂和黄酮等。其中冬凌草甲素和乙素为其抗肿瘤有效成分，有明显的杀菌作用，对各种癌病均有一定疗效，尤以早期食管癌疗效较明显。

冬凌草甲素和乙素在化学结构上有一定的差别。冬凌草乙素的结构中C14及C20之间多了一个氧桥，C14上缺乏一个—OH，这一结构的差异导致其抗肿瘤作用小于冬凌草甲素，但对免疫功能有兴奋作用。从体内分布来看，口服冬凌草甲素后15分钟血中即可测得同位素，半小时后达到高峰，吸收后很快分布到全身各个组织器官。冬凌草甲素以胆囊、肠道、肝脏、肾脏中放射含量较高；胰脏及食道次之；脑及骨中含量最少。24小时内从便及尿中排出占总放射量的53%。冬凌草乙素则以肺、胆囊和肝中含量较高；其次为肠、胰胃、肌肉、食管、胸腺；骨和脑中含量最少。24小时内从便及尿中排出占总放射量的25%。

Efficacy

对癌细胞的作用

　　 体外实验发现，冬凌草甲素及乙素对人体食管癌100细胞株及人体BEL-7402肝癌细胞株均有明显的细胞毒作用。冬凌草甲素10毫克/千克或乙素20毫克/千克腹腔注射，对L1210、P388、艾氏腹水癌（ECA）、肝癌及S180腹水型等都有明显抗肿瘤作用，使动物的平均存活期明显延长，部分动物可长期存活。对肝癌及组织细胞肉瘤实体型亦有明显抗肿瘤作用，对金黄色葡萄球菌甲型链球菌等上呼吸道菌株也有较强的杀菌作用。亚急性毒性实验证明，它们对大鼠或犬的骨髓、肝、肾等功能均无明显影响。

　　 实验发现，冬凌草甲素对G0期细胞的杀伤率为34.8%，说明冬凌草甲素对G0期细胞有一定的杀伤作用。冬凌草甲素对DNA、RNA及蛋白质合成均有抑制作用，对DNA合成的抑制作用先于对RNA合成的抑制。

对抗癌药物的协同作用

　　 冬凌草不仅本身有明显的抗肿瘤作用，而且可增强某些抗肿瘤药物的抗肿瘤作用。实验证明，冬凌草甲素可增强平阳霉素及顺氯氨铂（DDP）对艾氏腹水症、S180及P388白血病等病株的抗肿瘤作用，使荷瘤动物的存活期明显延长。冬凌草甲素与平阳霉素合用在体外可产生协同杀伤作用，对体内（P388、ECA）及体外（ECA）肿瘤细胞的DNA合成有明显的协同抑制作用，对RNA及蛋白质无协同抑制作用。合并用药对骨髓细胞也无抑制作用。说明冬凌草甲素与平阳霉素合并应用对骨髓细胞的DNA合成无明显影响。测定大鼠肝微粒体中细胞色素P450的含量时发现，冬凌草甲素与平阳霉素合用可明显诱导P450以及酯质过氧化物丙二苯的产生增加。平阳霉素在 NADPH-P450还原酶的催化下将Fe2+-BLM复合物还原为Fe2+-BLM，后者进一步与氧化结合形成O2-Fe2+-BLM，然后裂解成超氧化物阳离子自由基，引起酯质氧化及DNA新裂。冬凌草甲素可增强这一过程，从而加强其抗肿瘤作用。

Rabdosia rubescens is a herbal medicine used to treat esophageal cancer in China. In study, the sesquiterpene oridonin, an isoprenoid, was isolated from Rabdosia rubescens. Mass spectroscopy and carbon 13 NMR spectroscopy were used to identify the structure of the purified compound. It was then evaluated for biological activity against human cell lines derived from prostate (DU-145, LNCaP), breast (MCF-7), and ovarian (A2780 and PTX10) cancers. Oridonin exhibited anti-proliferative activity toward all cancer cell lines tested, with an IC50 estimated by the MTT cell viability assay ranging from 5.8+/-2.3 to 11.72+/-4.8 microM. Flow cytometric analysis demonstrated that oridonin induced a G1 phase arrest in androgen receptor-positive LNCaP cells containing wt p53, while it blocked the cell cycle at G2 and M phases in androgen receptor-negative DU-145 cells with mutated p53; the arrest in M was verified by examination of cell morphology and by the increased frequency of cells with Ser-10 phosphorylated histone H3. The increased incidence of apoptosis, identified by characteristic changes in cell morphology, was seen in tumor lines treated with oridonin. Notably, at concentrations that induced apoptosis among tumor cells, oridonin failed to induce apoptosis in cultures of normal human fibroblasts. Western blot analysis was used to determine the protein expression of cancer suppressor genes, p53 (wt) and Bax, and the proto-oncogene, Bcl-2 in LNCaP cells following treatment with oridonin. Oridonin up-regulated p53 and Bax and down-regulated Bcl-2 expression in a dose-dependent manner. To further explore the possible interaction between oridonin and DNA, its absorption spectrum was measured in the presence and absence of double stranded (ds) DNA. Spectral shifts and an increase in absorption band intensity were observed indicating interaction of oridonin with DNA bases. The nature of the binding is not clear at present though no evidence of histone H2AX phosphorylation on Ser-139 was apparent in DU-145 cells treated with oridonin that would indicate the induction of ds DNA breaks. In conclusion, oridonin inhibits cancer cell growth in a cell cycle specific manner and shifts the balance between pro- and anti-apoptotic proteins in favor of apoptosis. (source)

In study, we examined the inhibitory effects of certain individual components of PC-SPES on the in vitro proliferation of the human breast cancer cells MDA-MB231 and the human umbilical vein endothelial cells (HUVEC). Our data showed that individual components of PC-SPES had varying suppressive effects on cellular proliferation, and that Rabdosia rubescens appeared to be the most potent agent in these assays. Apoptosis was up-regulated by Rabdosia rubescens, as seen in the caspase-9 and TUNEL assays. These effects may be mediated via both the MAPK (mitogen-activated protein kinase) and the Akt kinase pathways. In mouse experiments, the extract from Rabdosia rubescens suppressed breast cancer xenograft size and decreased the tumor vessel density. We conclude that Rabdosia rubescens may potentially be used to treat or prevent breast cancer, and that the extract from this herbal source deserves further studies. (source)

From August 1974 to January 1987, 650 cases of moderately and advanced esophageal carcinoma were treated with a combination of chemotherapy and Rabdosia rubescens or Rabdosia rubescens and/or tradition chinese medicinal prescription. After treatment, 40 patients survived for over 5 years (5-year survival rate 6.15%): 32 for over 6 years, 23 for more than 10 years, 5 for more than 15 years and 20 die of tumors (16 cases) or other diseases (4 cases). There were 20 patients who are still living and some of them have been living for more than 18 years. Analyzing the data, it is believed that the age, the state of activity, the length of illness, the effectiveness of primary treatment, the multi-course extensive therapy, long-term maintenance treatment, etc, are all important factors affecting the results of drug treatment. (source)

IN VITRO:

1. Liu YQ, et al., Oridonin enhances phagocytosis of UV-irradiated apoptotic U937 cells. Biol Pharm Bull. 2005 Mar; 28(3):461-7.
2. Chen S, 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 Mar; 26(3):579-88.
3. Liu JJ, et al., Anti-proliferative effects of oridonin on SPC-A-1 cells and its mechanism of action. J Int Med Res. 2004 Nov-Dec; 32(6):617-25.
4. Sartippour MR, et al., Rabdosia rubescens inhibits breast cancer growth and angiogenesis. Int J Oncol. 2005 Jan; 26(1):121-7.
5. Zhang CL, et al., Oridonin induced A375-S2 cell apoptosis via bax-regulated caspase pathway activation, dependent on the cytochrome c/caspase-9 apoptosome. J Asian Nat Prod Res. 2004 Jun; 6(2):127-38.
6. Meade-Tollin LC, et al., Ponicidin and oridonin are responsible for the antiangiogenic activity of Rabdosia rubescens, a constituent of the herbal supplement PC SPES. J Nat Prod. 2004 Jan; 67(1):2-4.
7. Ikezoe T, et al., Oridonin induces growth inhibition and apoptosis of a variety of human cancer cells. Int J Oncol. 2003 Oct; 23(4):1187-93.
8. Hsieh TC, et al., Mechanism of action of herbal supplement PC-SPES: elucidation of effects of individual herbs of PC-SPES on proliferation and prostate specific gene expression in androgen-dependent LNCaP cells. Int J Oncol. 2002 Mar; 20(3):583-8.
9. de la Taille A, et al., Role of herbal compounds (PC-SPES) in hormone-refractory prostate cancer: two case reports. J Altern Complement Med. 2000 Oct; 6(5):449-51.
10. Gao ZG, et al., Synergistic effect of oridonin and cisplatin on cytotoxicity and DNA cross-link against mouse sarcoma S180 cells in culture. Zhongguo Yao Li Xue Bao. 1993 Nov; 14(6):561-4.
11. Wang RL, et al., [Potentiation by Rabdosia rubescens on chemotherapy of advanced esophageal carcinoma]. Zhonghua Zhong Liu Za Zhi. 1986 Jul; 8(4):297-9. Chinese.
    
    
    

IN VIVO:

1. de la Taille A, et al., Role of herbal compounds (PC-SPES) in hormone-refractory prostate cancer: two case reports. J Altern Complement Med. 2000 Oct; 6(5):449-51.
2. Gao ZG, et al., Synergistic effect of oridonin and cisplatin on cytotoxicity and DNA cross-link against mouse sarcoma S180 cells in culture. Zhongguo Yao Li Xue Bao. 1993 Nov; 14(6):561-4.
   
   
   

CLINICAL:

1. Wang RL. [A report of 40 cases of esophageal carcinoma surviving for more than 5 years after treatment with drugs]. Zhonghua Zhong Liu Za Zhi. 1993 Jul; 15(4):300-2. Chinese.
   

Safety

用药忌宜: 脾胃虚寒及血虚发热者忌服 。