原人参二醇及Compound K抑制肝细胞肝癌的作用及机制
The Inhibitory Effect of Protopanoxadiol and Compound K on Hepatocellular Carcinoma and the Underlying Mechanisms
DOI: 10.12677/TCM.2017.62018, PDF, HTML, XML, 下载: 1,624  浏览: 5,211  国家自然科学基金支持
作者: 张春蕾, 宋海燕, 季光*：上海中医药大学附属龙华医院脾胃病研究所；许阳贤：上海中医药大学附属龙华医院普外科
关键词: 肝细胞肝癌；原人参二醇；Compound K；Hepatocellular Carcinoma； Protopanoxadiol； Compound K
摘要: 中晚期肝癌及术后复发转移性肝癌目前仍然缺乏有效治疗手段。原人参二醇(protopanoxadiol, PPD)及人参皂苷Compound K是二醇型人参皂苷在体内的代谢产物。近年来多项研究发现这两种天然产物可通过诱导细胞凋亡、抑制细胞增殖、抑制血管生成、抑制转移等机制对多种肿瘤发挥抑瘤效应。其中对肝细胞肝癌的作用研究较多，抑癌效果尤为突出。本文就近年来PPD及Compound K抗肝细胞肝癌的作用和相关机制研究进行系统综述，以期有助于开发出有效治疗肝癌的天然药物。
Abstract: There is still no effective treatment available for advanced liver cancer or the recurrence and me-tastasis after surgical resection. Protopanoxadiol (PPD) and ginsenoside Compound K are the me-tabolites of protopanaxadiol-type ginsenosides in vivo. In recent years, a number of studies have found that these two kinds of natural products could play a role of tumor suppression through in-ducing cell apoptosis, inhibiting cell proliferation, inhibiting angiogenesis and limiting tumor cell metastasis. Among them, there are many studies focusing on the effect of PPD or Compound K on hepatocellular carcinoma (HCC), in which the anti-cancer effect is prominent. This paper reviews the recent studies on the role of PPD/Compound K in HCC and the related mechanisms, in order to ben-efit the development of new effective natural medicine to treat HCC.
文章引用：张春蕾, 宋海燕, 许阳贤, 季光. 原人参二醇及Compound K抑制肝细胞肝癌的作用及机制[J]. 中医学, 2017, 6(2): 104-109. https://doi.org/10.12677/TCM.2017.62018

参考文献

[1] (2014) Global Battle against Cancer Won’t Be Won with Treatment Alone—Effective Prevention Measures Urgently Needed to Prevent Cancer Crisis. Central European Journal of Public Health, 22, 23, 28.
[2] 梁宏元, 卢再鸣. 原发性肝癌综合介入治疗现状与困惑[J]. 临床肝胆病杂志, 2016(1): 44-48.
[3] 杨婉婷, 侯恩存. 原发性肝癌治疗的研究进展[J]. 现代肿瘤医学, 2016, 24(21): 3495-3499.
[4] Zhu, A.X. (2012) Molecularly Targeted Therapy for Advanced Hepatocellular Carcinoma in 2012: Current Status and Future Perspectives. Seminars in Oncology, 39, 493-502.
https://doi.org/10.1053/j.seminoncol.2012.05.014
[5] Personeni, N., Rimassa, L., Pressiani, T., et al. (2013) Molecular Determinants of Outcome in Sorafenib-Treated Patients with Hepatocellular Carci-noma. Journal of Cancer Research and Clinical Oncology, 139, 1179-1187.
https://doi.org/10.1007/s00432-013-1429-x
[6] Yun, T.K., Kim, S.H. and Lee, Y.S. (1995) Trial of a New Medium-Term Mod-el Using Benzo(a)pyrene Induced Lung Tumor in Newborn Mice. Anticancer Research, 15, 839-845.
[7] Huang, Y.C., Chen, C.T., Chen, S.C., et al. (2005) A Natural Compound (Ginsenoside Re) Isolated from Panax ginseng as a Novel Angiogenic Agent for Tissue Regeneration. Pharmaceutical Research, 22, 636-646.
https://doi.org/10.1007/s11095-005-2500-3
[8] Lee, S.J., Ko, W.G., Kim, J.H., et al. (2000) Induction of Apoptosis by a Novel Intestinal Metabolite of Ginseng Saponin via Cytochrome c-Mediated Activation of Caspase-3 Protease. Biochemical Pharmacology, 60, 677-685.
[9] 张虹, 付雯雯, 徐华丽, 等. 20(s)-原人参二醇、人参皂苷Rh2及人参皂苷Rg3抗肿瘤作用的对比[J]. 中国老年学杂志, 2014(17): 4911-4913.
[10] 郭亚雄, 刘艳波, 李德龙, 等. 20(s)-原人参二醇对前列腺癌RM-1细胞的生长抑制作用及其机制[J]. 吉林大学学报(医学版), 2010, 36(2): 349-353.
[11] 许宏, 杨佳卉, 杨景丽. 原人参二醇对人肺腺癌A549细胞作用的meta分析[J]. 甘肃科技, 2016, 32(4): 135-137.
[12] Tawab, M.A., Bahr, U., Karas, M., et al. (2003) Degradation of Ginsenosides in Humans after Oral Administration. Drug Metabolism & Disposition, 31, 1065-1071.
https://doi.org/10.1124/dmd.31.8.1065
[13] Bae, E.A., Choo, M.K., Park, E.K., et al. (2002) Metabolism of Ginsenoside R(c) by Human Intestinal Bacteria and Its Related Antiallergic Activity. Biological & Pharmaceutical Bulletin, 25, 743-747.
https://doi.org/10.1248/bpb.25.743
[14] Dong, H.J., Jiang, B.H., Han, Y., et al. (2010) Transformation of Compound K from Saponins in Leaves of Panaxnotoginseng by Immobilized β-Glucanase. Chinese Herbal Medicines, 2, 1044-1047.
[15] 刘娜, 朴虎日, 李宁, 等. 原人参二醇及其衍生物的化学与抗癌活性研究进展[J]. 中国药物化学杂志, 2008, 18(5): 384-388.
[16] 孟庆国, 衣松涛, 何杰, 等. 20(S)-原人参二醇及20(S)-原人参三醇新衍生物的设计、合成及体外抗肿瘤活性测定[C]//中国药学会. 创新药物及新品种研究、开发学术研讨会论文集: 2006年卷. 烟台: 中国药学会, 2006: 133-139.
[17] 张锐, 徐华丽, 于小风, 等. 20(S)-原人参二醇对SMMC-7721细胞体内外作用的研究[J]. 中国药理学通报, 2008, 24(11): 1504-1508.
[18] Zheng, Z.Z., Ming, Y.L., Chen, L.H., et al. (2014) Compound K-Induced Apoptosis of Human Hepatocellular Carcinoma MHCC97-H Cells in Vitro. Oncology Reports, 32, 325-331.
[19] Oh, S.H., Yin, H.Q. and Lee, B.H. (2004) Role of the Fas/Fas Ligand Death Receptor Pathway in Ginseng Saponin Metabolite-Induced Apoptosis in Hepg2 Cells. Archives of Pharmacal Research, 27, 402-406.
https://doi.org/10.1007/BF02980081
[20] Liu, X., Kim, C.N., Yang, J., et al. (1996) Induction of Apoptotic Program in Cell-Free Extracts: Requirement for dATP and Cytochrome c. Cell, 86, 147-157.
https://doi.org/10.1016/S0092-8674(00)80085-9
[21] 明艳林, 郑志忠, 陈良华, 等. 人参皂苷IH901抗肝癌生长及其侵袭转移的作用机理[J]. 中国科学: 生命科学, 2011, 41(3): 219-225.
[22] Song, G., Chen, G.G., Yun, J.P., et al. (2009) Association of p53 with Bid Induces Cell Death in Response to Etopo-side Treatment in Hepatocellular Carcinoma. Current Cancer Drug Targets, 9, 871-880.
https://doi.org/10.2174/156800909789760302
[23] Song, G., Guo, S., Wang, W., et al. (2010) Intestinal Metabolite Compound K of Ginseng Saponin Potently Attenuates Metastatic Growth of Hepatocellular Carcinoma by Augmenting Apoptosis via a Bid-Mediated Mitochondrial Pathway. Journal of Agricultural & Food Chemistry, 58, 12753-12760.
https://doi.org/10.1021/jf103814f
[24] Cho, S.H., Chung, K.S., Choi, J.H., et al. (2009) Compound K, a Metabolite of Ginseng Saponin, Induces Apoptosis via Caspase-8-Dependent Pathway in HL-60 Human Leukemia Cells. BMC Cancer, 9, 449.
[25] Zhu, G.Y., Li, Y.W., Tse, A.K.W., et al. (2011) 20(S)-Protopanaxadiol, a Metabolite of Ginsenosides, Induced Cell Apoptosis through En-doplasmic Reticulum Stress in Human Hepatocarcinoma HepG2 Cells. European Journal of Pharmacology, 668, 88-98.
[26] Mochi-zuki, M., Yoo, Y.C., Matsuzawa, K., et al. (1995) Inhibitory Effect of Tumor Metastasis in Mice by Saponins, Ginsenoside-Rb2, 20(R)- and 20(S)-Ginsenoside-Rg3, of Red Ginseng. Biological & Pharmaceutical Bulletin, 18, 1197-1202.
https://doi.org/10.1248/bpb.18.1197
[27] Ming, Y.L., Song, G., Chen, L.H., et al. (2007) Anti-Proliferation and Apoptosis Induced by a Novel Intestinal Metabolite of Ginseng Saponin in Human Hepatocellular Carcinoma Cells. Cell Biology International, 31, 1265-1273.
https://doi.org/10.1016/j.cellbi.2007.05.005
[28] Ming, Y.L., Zheng, Z.Z., Chen, L.H., et al. (2007) Apoptosis Induced by a Novel Intestinal Metabolite of Ginseng Saponin in Human Hepatocellular Carcinoma BEL-7402 Cells. Chinese Traditional & Herbal Drugs, 38, 1511-1514.
[29] Saiki, I. (2007) In Vivo Anti-Metastatic Action of Ginseng Saponins Is Based on Their Intestinal Bacterial Metabolites after Oral Administration. Journal of Ginseng Research, 31, 1-13.
https://doi.org/10.5142/JGR.2007.31.1.001
[30] Usami, Y., Liu, Y.N., Lin, A.S., et al. (2008) Antitumor Agents. 261. 20(S)-Protopanaxadiol and 20(S)-Protopanaxa- triol as Antiangiogenic Agents and Total Assignment of (1)H NMR Spectra. Journal of Natural Products, 71, 478-481.
https://doi.org/10.1021/np070613q
[31] 冷吉燕, 付军, 王继萍. 20(s)-原人参二醇对肝癌血管内皮生长因子及碱性成纤维细胞生长因子蛋白表达的影响[J]. 临床肝胆病杂志, 2008, 24(1): 42-43.
[32] 张国成, 秦俊杰, 冷吉燕. 20(S)-原人参二醇抑制肝癌血管内皮生长因子及其基因的表达[J]. 中国老年学杂志, 2006, 26(7): 945-946.
[33] 秦俊杰, 杨艳秋, 李颖新, 等. 20(S)-原人参二醇对肝癌间质血管密度和肿瘤细胞增殖活性的影响[J]. 临床肝胆病杂志, 2006, 22(4): 260-261.
[34] Ming, Y., Chen, Z., Chen, L., et al. (2010) Ginsenoside Compound K Attenuates Metastatic Growth of Hepatocellular Carcinoma, Which Is Associated with the Translocation of Nuclear Factor-κB p65 and Reduction of Matrix Metalloproteinase-2/9. Planta Medica, 77, 428-433.
https://doi.org/10.1055/s-0030-1250454
[35] Zhao, Y., Bu, L., Yan, H., et al. (2009) 20S-Protopanaxadiol Inhibits P-Glycoprotein in Multidrug Resistant Cancer Cells. Planta Medica, 75, 1124-1128.
https://doi.org/10.1055/s-0029-1185477
[36] 明艳林, 郑志忠, 陈良华, 等. 20-O-β-D-吡喃葡萄糖苷-20(S)-原人参二醇对抗肝癌药物的增敏作用研究[J]. 中草药, 2010, 41(6): 935-938.
[37] 陈明侠, 徐华丽, 于小风, 等. 20(S)-原人参二醇的抗肿瘤及免疫调节作用研究[J]. 中国药师, 2007, 10(12): 65- 68.
[38] Kang, S., Kim, J.E., Song, N.R., et al. (2014) The Ginsenoside 20-O-β-D-Glucopyranosyl-20(S)-Protopanaxadiol Induces Autophagy and Apoptosis in Human Melanoma via AMPK/JNK Phosphorylation. PLoS ONE, 9, e104305.
https://doi.org/10.1371/journal.pone.0104305