人参皂苷Rh_2抗肿瘤机制及药物递送研究进展
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摘要
人参皂苷Rh_2(G-Rh_2)具有较强的抗肿瘤活性,对肺癌、肝癌、乳腺癌、结肠癌等多种癌症均具有抑制作用,且当其与化疗药物联用时能逆转化疗药物的多药耐药性。但由于G-Rh_2单体水溶性较差,限制了其临床应用,故常通过药物递送系统来改善其生物利用度。本文对G-Rh_2的抗肿瘤作用机制以及药物递送系统进行综述,为G-Rh_2的深入研究提供参考。
Ginsenoside Rh_2(G-Rh_2)has strong anti-tumor activity and inhibits many kinds of cancers,such as lung cancer,liver cancer,breast cancer and colon cancer. It can also reverse the multidrug resistance when it was used in combination with some anticancer drugs. However,its clinical application is limited due to its low water solubility. Therefore,drug delivery systems are usually used to improve its bioavailability. This paper reviews research development of the antitumor mechanisms and the drug delivery systems of G-Rh_2 to provide a reference for further studies in future.
Ginsenoside Rh_2(G-Rh_2)has strong anti-tumor activity and inhibits many kinds of cancers,such as lung cancer,liver cancer,breast cancer and colon cancer. It can also reverse the multidrug resistance when it was used in combination with some anticancer drugs. However,its clinical application is limited due to its low water solubility. Therefore,drug delivery systems are usually used to improve its bioavailability. This paper reviews research development of the antitumor mechanisms and the drug delivery systems of G-Rh_2 to provide a reference for further studies in future.
引文
[1] Zarezardini H,Taherikafrani A,Amiri A,et al. New generation of drug delivery systems based on ginsenoside Rh2-,lysine-and arginine-treated highly porous graphene for improving anticancer activity[J]. Sci Rep,2018,8(1):586.
[2] Jie L,Shiono J,Shimizu K,et al. 20(R)-Ginsenoside Rh2,not20(S),is a selective osteoclastgenesis inhibitor without any cytotoxicity[J]. Bioorg Med Chem Lett,2009,19(12):3320-3323.
[3] Shi Q,Li J,Feng Z,et al. Effect of ginsenoside Rh2on the migratory ability of HepG2 liver carcinoma cells:recruiting histone deacetylase and inhibiting activator protein 1 transcription factors[J]. Mol Med Rep,2014,10(4):1779-1785.
[4]王琳,杨智钧,向敏,等.甘草次酸修饰的人参皂苷Rh2脂质体的制备及其体外评价[J].中国实验方剂学杂志,2015,21(5):29-32.
[5] Hadinoto K,Sundaresan A,Cheow WS. Lipid-polymer hybrid nanoparticles as a new generation therapeutic delivery platform:a review[J]. Eur J Pharm Biopharm,2013,85(3 Pt A):427-443.
[6] Singh P,Kim YJ,Singh H,et al. In situ preparation of watersoluble ginsenoside Rh2-entrapped bovine serum albumin nanoparticles:in vitro cytocompatibility studies[J]. Int J Nanomed,2017,12:4073-4084.
[7]邹亮,符佳,李维,等.人参皂苷Rh2脂质纳米粒的制备表征及冰片对其抗肿瘤活性的协同作用研究[J].中国中药杂志,2016,41(7):1235-1240.
[8] Tian X,Ma P,Sui CG,et al. Suppression of tumor necrosis factor receptor-associated protein 1 expression induces inhibition of cell proliferation and tumor growth in human esophageal cancer cells[J]. FEBS J,2014,281(12):2805-2819.
[9]喻笛.人参皂苷Rh2诱导三阴性乳腺癌MDA-MB-231细胞凋亡机制的研究[D].长春:吉林大学,2015.
[10] An IS,An S,Kwon KJ,et al. Ginsenoside Rh2mediates changes in the microRNA expression profile of human non-small cell lung cancer A549 cells[J]. Oncol Rep,2013,29(2):523-528.
[11] Li Q,Li Y,Wang X,et al. Co-treatment with ginsenoside Rh2and betulinic acid synergistically induces apoptosis in human cancer cells in association with enhanced capsase-8 activation,bax translocation,and cytochrome c release[J]. Mol Carcinog,2011,50(10):760-769.
[12] Li P,Zhou X,Qu D,et al. Preliminary study on fabrication,characterization and synergistic anti-lung cancer effects of selfassembled micelles of covalently conjugated celastrol-polyethylene glycol-ginsenoside Rh2[J]. Drug Deliv,2017,24(1):834-845.
[13] Shi Q,Shi X,Zuo G,et al. Anticancer effect of 20(S)-ginsenoside Rh2on HepG2 liver carcinoma cells:activating GSK-3βand degradingβ-catenin[J]. Oncol Rep,2016,36(4):2059-2070.
[14] Shi Q,Li J,Feng Z,et al. Effect of ginsenoside Rh2on the migratory ability of HepG2 liver carcinoma cells:recruiting histone deacetylase and inhibiting activator protein 1 transcription factors[J]. Mol Med Rep,2014,10(4):1779.
[15] Wen X,Zhang HD,Zhao L,et al. Ginsenoside Rh2differentially mediates microRNA expression to prevent chemoresistance of breast cancer[J]. Asian Pac J Cancer Prev,2015,16(3):1105-1109.
[16] Zhou B,Xiao X,Xu L,et al. A dynamic study on reversal of multidrug resistance by ginsenoside Rh2in adriamycin-resistant human breast cancer MCF-7 cells[J]. Talanta,2012,88(1):345-351.
[17] Zhang J,Zhou F,Wu X,et al. Cellular pharmacokinetic mechanisms of adriamycin resistance and its modulation by 20(S)-ginsenoside Rh2in MCF-7/Adr cells[J]. Br J Pharmacol,2011,165(1):120-134.
[18] Yang J,Yuan D,Xing T,et al. Ginsenoside Rh2inhibiting HCT116 colon cancer cell proliferation through blocking PDZbinding kinase/T-LAK cell-originated protein kinase[J]. J Ginseng Res,2016,40(4):400-408.
[19] Gu Y,Wang GJ,Sun JG,et al. Pharmacokinetic characterization of ginsenoside Rh2,an anticancer nutrient from ginseng,in rats and dogs[J]. Food Chem Toxicol,2009,47(9):2257-2268.
[20] Chung KS,Cho SH,Shin JS,et al. Ginsenoside Rh2induces cell cycle arrest and differentiation in human leukemia cells by upregulating TGF-βexpression[J]. Carcinogenesis,2013,34(2):331-340.
[21] Wang X,Wang Y. Ginsenoside Rh2mitigates pediatric leukemia through suppression of Bcl-2 in leukemia cells[J]. Cell Physiol Biochem,2015,37(2):641-50.
[22]武剑,王炜,李晓.人参皂苷Rh2通过GATA-1诱导K562细胞红系分化作用的研究[J].中国中医急症,2014,23(8):1451-1452.
[23] Xia T,Wang JC,Xu W,et al. 20(S)-Ginsenoside Rh2induces apoptosis in human leukaemia Reh cells through mitochondrial signaling pathways[J]. Biol Pharm Bull,2014,37(2):248-254.
[24]游智梅,陈地龙,魏强,等.人参皂苷单体Rh2抑制人白血病KG1-α细胞增殖并促进其凋亡[J].细胞与分子免疫学杂志,2014,30(6):565-568.
[25]冯子强.中药有效成分抑制肿瘤细胞迁移和逆转多药耐药的实验研究[D].重庆:重庆医科大学,2015.
[26]徐晓军,石淑文,汤永民,等.人参皂苷Rh2抗白血病多药耐药细胞K562/VCR作用研究[J].中草药,2010,41(7):1131-1135.
[27]谢炜,罗阔,韩萍.人参皂苷Rh2对肝癌细胞表皮生长因子受体表达水平的影响[J].免疫学杂志,2013,29(6):490-493.
[28]冯子强,左国伟,石庆强,等.人参皂苷Rh2抑制肝癌HepG2细胞迁移的实验研究[J].中国免疫学杂志,2015,31(1):61-65.
[29]石庆强,左国伟,冯子强,等.人参皂苷Rh2通过激活Gsk-3β削弱β-catenin在肝癌HepG2细胞中的作用[J].中国免疫学杂志,2015,8(31):1476-1485.
[30] Yi JS,Choo HJ,Cho BR,et al. Ginsenoside Rh2induces ligandindependent Fas activation via lipid raft disruption[J]. Biochem Biophys Res Commun,2009,385(2):154-159.
[31]李清,王晓宇,李杨,等.人参皂甙Rh2提高人源肝癌细胞HepG2对桦木酸敏感性的作用机制[J].中国生物制品学杂志,2011,24(5):531-533.
[32] Wang H,Zhou B,Guo X,et al. Effect of ginsenoside Rh2on cell proliferation and cytoskeleton in hepatocarcinoma SMMC-7721 cells[J]. J Pathophysiol,2011,27(6):1226-1229.
[33]金美顺,朴丽花,韩春姬,等.人参皂苷Rh2对人乳腺癌MCF7/AdrR细胞增殖和凋亡的影响[J].基础研究,2010,26(12):923-927.
[34]李萍,陈善.人参皂苷Rh2逆转MCF-7/ADM多药耐药性的研究[J].中国医药指南,2013,11(21):8-10.
[35]朴丽花,蔡英兰,张默函,等.人参皂苷Rh2与PI3K/AKT信号通路抑制剂LY294002对乳腺癌细胞转移和侵袭的影响[J].中国药房,2013,24(43):4050-4052.
[36]张春晶,丁海涛,侯金才. S型与R型人参皂苷Rh2对人肺腺癌A549细胞增殖和凋亡的影响[J].中国中药杂志,2011,36(12):1670-1674.
[37]齐晓丹,张春晶,于海涛,等. S型与R型人参皂苷Rh2诱导人肺腺癌A549细胞凋亡的体外研究[J].中国医药指南,2011,9(21):8-10.
[38] Ge G,Yan Y,Cai H. Ginsenoside Rh2inhibited proliferation by inducing ROS mediated ER stress dependent apoptosis in lung cancer cells[J]. Biol Pharm Bull,2017,40(12):2117-2124.
[39]李秋影,颜璐璐,马晓慧,等. 20(S)-人参皂苷Rh2对人结肠癌细胞增殖和周期的影响[J].中成药,2011,33(11):1874-1878.
[40] Yang J,Yuan D,Xing T,et al. Ginsenoside Rh2inhibiting HCT116 colon cancer cell proliferation through blocking PDZbinding kinase/T-LAK cell-originated protein kinase[J]. J Ginseng Res,2016,40(4):400-408.
[41]何静春,李峰,赵丽娟.人参单体皂苷Rh2与顺铂联合应用诱导小鼠前列腺癌凋亡[J].中国老年学杂志,2014,34(6):1555-1557.
[42] Xie HT,Wang GJ,Lv H,et al. Development of a HPLC-MS assay for ginsenoside Rh2,a new anti-tumor substance from natural product and its pharacokinetic study in dogs[J]. Eur J Drug Metab Pharmacokinet,2005,30(1/2):63-67.
[43]张斌,谷克仁,潘丽,等.脂质体的性质及制备方法的研究进展[J].粮食与油脂,2015,28(10):17-20.
[44]段兰兰,曾繁明,刘悦,等.纳米微球在药物载体领域的研究进展[J].胶体与聚合物,2015,33(4):175-177.
[45]程海鹰,郑定容.人参皂苷白蛋白纳米微球对人肺腺癌A549细胞生长抑制作用研究[J].黑龙江医学,2014,38(10):1138-1140.
[46] Caboi F,Lazzari P,Pani L,et al. Effect of 1-butanol on the microstructure of lecithin/water/tripalmitin system[J]. Chem Phys Lipids,2005,135(2):147-156.
[47] Yang F,Zhou J,Hu X,et al. Preparation and evaluation of selfmicroemulsions for improved bioavailability of ginsenoside-Rh1and Rh2[J]. Drug Deliv Transl Res,2017,7(5):1-7.
[48] Qu D,Wang L,Liu M,et al. Oral nanomedicine based on multicomponent microemulsions for drug-resistant breast cancer treatment[J]. Biomacromolecules,2017,18(4):1268-1280.
[49] Tawarah KM,Khouri SJ. Determination of the stability and stoichiometry of p-methyl red inclusion complexes withγ-cyclodextrin[J]. Dyes Pigm,2000,45(3):229-233.
[50]张蓓,林东海,肖楠,等.人参皂苷Rh2-羟丙基-β-环糊精包合物的鉴定和热力学参数考察[J].中草药,2007,38(11):1635-1637.
[51] He L,Lee J,Jang JH,et al. Ginsenoside Rh2inhibits osteoclastogenesis through down-regulation of NF-κB,NFATc1 and cFos[J]. Bone,2012,50(6):1207-1213.
[2] Jie L,Shiono J,Shimizu K,et al. 20(R)-Ginsenoside Rh2,not20(S),is a selective osteoclastgenesis inhibitor without any cytotoxicity[J]. Bioorg Med Chem Lett,2009,19(12):3320-3323.
[3] Shi Q,Li J,Feng Z,et al. Effect of ginsenoside Rh2on the migratory ability of HepG2 liver carcinoma cells:recruiting histone deacetylase and inhibiting activator protein 1 transcription factors[J]. Mol Med Rep,2014,10(4):1779-1785.
[4]王琳,杨智钧,向敏,等.甘草次酸修饰的人参皂苷Rh2脂质体的制备及其体外评价[J].中国实验方剂学杂志,2015,21(5):29-32.
[5] Hadinoto K,Sundaresan A,Cheow WS. Lipid-polymer hybrid nanoparticles as a new generation therapeutic delivery platform:a review[J]. Eur J Pharm Biopharm,2013,85(3 Pt A):427-443.
[6] Singh P,Kim YJ,Singh H,et al. In situ preparation of watersoluble ginsenoside Rh2-entrapped bovine serum albumin nanoparticles:in vitro cytocompatibility studies[J]. Int J Nanomed,2017,12:4073-4084.
[7]邹亮,符佳,李维,等.人参皂苷Rh2脂质纳米粒的制备表征及冰片对其抗肿瘤活性的协同作用研究[J].中国中药杂志,2016,41(7):1235-1240.
[8] Tian X,Ma P,Sui CG,et al. Suppression of tumor necrosis factor receptor-associated protein 1 expression induces inhibition of cell proliferation and tumor growth in human esophageal cancer cells[J]. FEBS J,2014,281(12):2805-2819.
[9]喻笛.人参皂苷Rh2诱导三阴性乳腺癌MDA-MB-231细胞凋亡机制的研究[D].长春:吉林大学,2015.
[10] An IS,An S,Kwon KJ,et al. Ginsenoside Rh2mediates changes in the microRNA expression profile of human non-small cell lung cancer A549 cells[J]. Oncol Rep,2013,29(2):523-528.
[11] Li Q,Li Y,Wang X,et al. Co-treatment with ginsenoside Rh2and betulinic acid synergistically induces apoptosis in human cancer cells in association with enhanced capsase-8 activation,bax translocation,and cytochrome c release[J]. Mol Carcinog,2011,50(10):760-769.
[12] Li P,Zhou X,Qu D,et al. Preliminary study on fabrication,characterization and synergistic anti-lung cancer effects of selfassembled micelles of covalently conjugated celastrol-polyethylene glycol-ginsenoside Rh2[J]. Drug Deliv,2017,24(1):834-845.
[13] Shi Q,Shi X,Zuo G,et al. Anticancer effect of 20(S)-ginsenoside Rh2on HepG2 liver carcinoma cells:activating GSK-3βand degradingβ-catenin[J]. Oncol Rep,2016,36(4):2059-2070.
[14] Shi Q,Li J,Feng Z,et al. Effect of ginsenoside Rh2on the migratory ability of HepG2 liver carcinoma cells:recruiting histone deacetylase and inhibiting activator protein 1 transcription factors[J]. Mol Med Rep,2014,10(4):1779.
[15] Wen X,Zhang HD,Zhao L,et al. Ginsenoside Rh2differentially mediates microRNA expression to prevent chemoresistance of breast cancer[J]. Asian Pac J Cancer Prev,2015,16(3):1105-1109.
[16] Zhou B,Xiao X,Xu L,et al. A dynamic study on reversal of multidrug resistance by ginsenoside Rh2in adriamycin-resistant human breast cancer MCF-7 cells[J]. Talanta,2012,88(1):345-351.
[17] Zhang J,Zhou F,Wu X,et al. Cellular pharmacokinetic mechanisms of adriamycin resistance and its modulation by 20(S)-ginsenoside Rh2in MCF-7/Adr cells[J]. Br J Pharmacol,2011,165(1):120-134.
[18] Yang J,Yuan D,Xing T,et al. Ginsenoside Rh2inhibiting HCT116 colon cancer cell proliferation through blocking PDZbinding kinase/T-LAK cell-originated protein kinase[J]. J Ginseng Res,2016,40(4):400-408.
[19] Gu Y,Wang GJ,Sun JG,et al. Pharmacokinetic characterization of ginsenoside Rh2,an anticancer nutrient from ginseng,in rats and dogs[J]. Food Chem Toxicol,2009,47(9):2257-2268.
[20] Chung KS,Cho SH,Shin JS,et al. Ginsenoside Rh2induces cell cycle arrest and differentiation in human leukemia cells by upregulating TGF-βexpression[J]. Carcinogenesis,2013,34(2):331-340.
[21] Wang X,Wang Y. Ginsenoside Rh2mitigates pediatric leukemia through suppression of Bcl-2 in leukemia cells[J]. Cell Physiol Biochem,2015,37(2):641-50.
[22]武剑,王炜,李晓.人参皂苷Rh2通过GATA-1诱导K562细胞红系分化作用的研究[J].中国中医急症,2014,23(8):1451-1452.
[23] Xia T,Wang JC,Xu W,et al. 20(S)-Ginsenoside Rh2induces apoptosis in human leukaemia Reh cells through mitochondrial signaling pathways[J]. Biol Pharm Bull,2014,37(2):248-254.
[24]游智梅,陈地龙,魏强,等.人参皂苷单体Rh2抑制人白血病KG1-α细胞增殖并促进其凋亡[J].细胞与分子免疫学杂志,2014,30(6):565-568.
[25]冯子强.中药有效成分抑制肿瘤细胞迁移和逆转多药耐药的实验研究[D].重庆:重庆医科大学,2015.
[26]徐晓军,石淑文,汤永民,等.人参皂苷Rh2抗白血病多药耐药细胞K562/VCR作用研究[J].中草药,2010,41(7):1131-1135.
[27]谢炜,罗阔,韩萍.人参皂苷Rh2对肝癌细胞表皮生长因子受体表达水平的影响[J].免疫学杂志,2013,29(6):490-493.
[28]冯子强,左国伟,石庆强,等.人参皂苷Rh2抑制肝癌HepG2细胞迁移的实验研究[J].中国免疫学杂志,2015,31(1):61-65.
[29]石庆强,左国伟,冯子强,等.人参皂苷Rh2通过激活Gsk-3β削弱β-catenin在肝癌HepG2细胞中的作用[J].中国免疫学杂志,2015,8(31):1476-1485.
[30] Yi JS,Choo HJ,Cho BR,et al. Ginsenoside Rh2induces ligandindependent Fas activation via lipid raft disruption[J]. Biochem Biophys Res Commun,2009,385(2):154-159.
[31]李清,王晓宇,李杨,等.人参皂甙Rh2提高人源肝癌细胞HepG2对桦木酸敏感性的作用机制[J].中国生物制品学杂志,2011,24(5):531-533.
[32] Wang H,Zhou B,Guo X,et al. Effect of ginsenoside Rh2on cell proliferation and cytoskeleton in hepatocarcinoma SMMC-7721 cells[J]. J Pathophysiol,2011,27(6):1226-1229.
[33]金美顺,朴丽花,韩春姬,等.人参皂苷Rh2对人乳腺癌MCF7/AdrR细胞增殖和凋亡的影响[J].基础研究,2010,26(12):923-927.
[34]李萍,陈善.人参皂苷Rh2逆转MCF-7/ADM多药耐药性的研究[J].中国医药指南,2013,11(21):8-10.
[35]朴丽花,蔡英兰,张默函,等.人参皂苷Rh2与PI3K/AKT信号通路抑制剂LY294002对乳腺癌细胞转移和侵袭的影响[J].中国药房,2013,24(43):4050-4052.
[36]张春晶,丁海涛,侯金才. S型与R型人参皂苷Rh2对人肺腺癌A549细胞增殖和凋亡的影响[J].中国中药杂志,2011,36(12):1670-1674.
[37]齐晓丹,张春晶,于海涛,等. S型与R型人参皂苷Rh2诱导人肺腺癌A549细胞凋亡的体外研究[J].中国医药指南,2011,9(21):8-10.
[38] Ge G,Yan Y,Cai H. Ginsenoside Rh2inhibited proliferation by inducing ROS mediated ER stress dependent apoptosis in lung cancer cells[J]. Biol Pharm Bull,2017,40(12):2117-2124.
[39]李秋影,颜璐璐,马晓慧,等. 20(S)-人参皂苷Rh2对人结肠癌细胞增殖和周期的影响[J].中成药,2011,33(11):1874-1878.
[40] Yang J,Yuan D,Xing T,et al. Ginsenoside Rh2inhibiting HCT116 colon cancer cell proliferation through blocking PDZbinding kinase/T-LAK cell-originated protein kinase[J]. J Ginseng Res,2016,40(4):400-408.
[41]何静春,李峰,赵丽娟.人参单体皂苷Rh2与顺铂联合应用诱导小鼠前列腺癌凋亡[J].中国老年学杂志,2014,34(6):1555-1557.
[42] Xie HT,Wang GJ,Lv H,et al. Development of a HPLC-MS assay for ginsenoside Rh2,a new anti-tumor substance from natural product and its pharacokinetic study in dogs[J]. Eur J Drug Metab Pharmacokinet,2005,30(1/2):63-67.
[43]张斌,谷克仁,潘丽,等.脂质体的性质及制备方法的研究进展[J].粮食与油脂,2015,28(10):17-20.
[44]段兰兰,曾繁明,刘悦,等.纳米微球在药物载体领域的研究进展[J].胶体与聚合物,2015,33(4):175-177.
[45]程海鹰,郑定容.人参皂苷白蛋白纳米微球对人肺腺癌A549细胞生长抑制作用研究[J].黑龙江医学,2014,38(10):1138-1140.
[46] Caboi F,Lazzari P,Pani L,et al. Effect of 1-butanol on the microstructure of lecithin/water/tripalmitin system[J]. Chem Phys Lipids,2005,135(2):147-156.
[47] Yang F,Zhou J,Hu X,et al. Preparation and evaluation of selfmicroemulsions for improved bioavailability of ginsenoside-Rh1and Rh2[J]. Drug Deliv Transl Res,2017,7(5):1-7.
[48] Qu D,Wang L,Liu M,et al. Oral nanomedicine based on multicomponent microemulsions for drug-resistant breast cancer treatment[J]. Biomacromolecules,2017,18(4):1268-1280.
[49] Tawarah KM,Khouri SJ. Determination of the stability and stoichiometry of p-methyl red inclusion complexes withγ-cyclodextrin[J]. Dyes Pigm,2000,45(3):229-233.
[50]张蓓,林东海,肖楠,等.人参皂苷Rh2-羟丙基-β-环糊精包合物的鉴定和热力学参数考察[J].中草药,2007,38(11):1635-1637.
[51] He L,Lee J,Jang JH,et al. Ginsenoside Rh2inhibits osteoclastogenesis through down-regulation of NF-κB,NFATc1 and cFos[J]. Bone,2012,50(6):1207-1213.