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Current Molecular Pharmacology

Author(s): Xin-Ling He, Xiao-Huang Xu, Jia-Jie Shi, Mingqing Huang, Yitao Wang, Xiuping Chen and Jin-Jian Lu*

DOI: 10.2174/1874467214666210309115105

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Anticancer Effects of Ginsenoside Rh2: A Systematic Review

Article ID: e040122192163 Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: As one of the effective pharmacological constituents of Ginseng Radix et Rhizoma, ginsenoside Rh2 (Rh2) exerts a remarkable anticancer effect on various cancer cell lines in vitro and strongly inhibits tumor growth in vivo without severe toxicity.

Objective: This article reviewed existing evidence supporting the anticancer effects of Rh2 to classify and conclude previous and current knowledge on the mechanisms and therapeutic effects of Rh2, as well as to promote the clinical application of this natural product.

Conclusion: This article reviewed the anticancer efficacies and mechanisms of Rh2, including the induction of cell cycle arrest and programmed cell death, repression of metastasis, alleviation of drug resistance, and regulation of the immune system. Finally, this paper discussed the research and application prospects of Rh2.

Keywords: Ginseng, ginsenoside Rh2, cancer, cytotoxicity, mechanism, natural compound

Graphical Abstract

[1]
Li, X.Y.; Sun, L.W.; Zhao, D.Q. Current Status and Problem-Solving Strategies for Ginseng Industry. Chin. J. Integr. Med., 2019, 25(12), 883-886.
[http://dx.doi.org/10.1007/s11655-019-3046-2] [PMID: 31630359]
[2]
Chen, W; Balan, P. Analysis of Ginsenoside Content (Panax ginseng) from Different Regions. Molecules, 2019, 24(19), 3491.
[3]
Xiang, Y.Z.; Shang, H.C.; Gao, X.M.; Zhang, B.L. A comparison of the ancient use of ginseng in traditional Chinese medicine with modern pharmacological Molecules experiments and clinical trials. Phytother. Res., 2008, 22(7), 851-858.
[http://dx.doi.org/10.1002/ptr.2384] [PMID: 18567057]
[4]
Yuan, J.; Chen, Y.; Liang, J.; Wang, C.Z.; Liu, X.; Yan, Z.; Tang, Y.; Li, J.; Yuan, C.S. Component analysis and target cell-based neuroactivity screening of Panax ginseng by ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2016, 1038, 1-11.
[http://dx.doi.org/10.1016/j.jchromb.2016.10.014] [PMID: 27776327]
[5]
Shin, B.K.; Kwon, S.W.; Park, J.H. Chemical diversity of ginseng saponins from Panax ginseng. J. Ginseng Res., 2015, 39(4), 287-298.
[http://dx.doi.org/10.1016/j.jgr.2014.12.005] [PMID: 26869820]
[6]
Ahuja, A.; Kim, J.H.; Kim, J.H.; Yi, Y.S.; Cho, J.Y. Functional role of ginseng-derived compounds in cancer. J. Ginseng Res., 2018, 42(3), 248-254.
[http://dx.doi.org/10.1016/j.jgr.2017.04.009] [PMID: 29983605]
[7]
Cheng, Z.; Zhang, M.; Ling, C.; Zhu, Y.; Ren, H.; Hong, C.; Qin, J.; Liu, T.; Wang, J. Neuroprotective Effects of Ginsenosides against Cerebral Ischemia. Molecules, 2019, 24(6), 1102.
[http://dx.doi.org/10.3390/molecules24061102] [PMID: 30897756]
[8]
Liu, Y.; Deng, J.; Fan, D. Ginsenoside Rk3 ameliorates high-fat-diet/streptozocin induced type 2 diabetes mellitus in mice via the AMPK/Akt signaling pathway. Food Funct., 2019, 10(5), 2538-2551.
[http://dx.doi.org/10.1039/C9FO00095J] [PMID: 30993294]
[9]
Kim, J.H. Pharmacological and medical applications of Panax ginseng and ginsenosides: a review for use in cardiovascular diseases. J. Ginseng Res., 2018, 42(3), 264-269.
[http://dx.doi.org/10.1016/j.jgr.2017.10.004] [PMID: 29983607]
[10]
Guo, Y.H.; Kuruganti, R.; Gao, Y. Recent Advances in Ginsenosides as Potential Therapeutics Against Breast Cancer. Curr. Top. Med. Chem., 2019, 19(25), 2334-2347.
[http://dx.doi.org/10.2174/1568026619666191018100848] [PMID: 31648643]
[11]
Gao, S.H.; Zhao, D.D.; Bai, Y.; Wu, R.; Mo, F.F.; Liu, C.Y. Effects of ginsenoside Rb1 on skeletal muscle insulin resistance and adenosine monophosphate-activated protein kinase signaling pathway in obese mice. World J. Tradit. Chin. Med., 2019, 5(1), 42.
[http://dx.doi.org/10.4103/wjtcm.wjtcm_3_19]
[12]
Luo, H.; Vong, C.T.; Chen, H.; Gao, Y.; Lyu, P.; Qiu, L.; Zhao, M.; Liu, Q.; Cheng, Z.; Zou, J.; Yao, P.; Gao, C.; Wei, J.; Ung, C.O.L.; Wang, S.; Zhong, Z.; Wang, Y. Naturally occurring anti- cancer compounds: shining from Chinese herbal medicine. Chin. Med., 2019, 14(1), 48.
[http://dx.doi.org/10.1186/s13020-019-0270-9] [PMID: 31719837]
[13]
Xu, X.H.; Li, T.; Fong, C.M.V.; Chen, X.; Chen, X.J.; Wang, Y.T.; Huang, M.Q.; Lu, J.J. Saponins from Chinese Medicines as Anticancer Agents. Molecules, 2016, 21(10), 1326.
[http://dx.doi.org/10.3390/molecules21101326] [PMID: 27782048]
[14]
Bae, E.A.; Han, M.J.; Choo, M.K.; Park, S.Y.; Kim, D.H. Metabolism of 20(S)- and 20(R)-ginsenoside Rg3 by human intestinal bacteria and its relation to in vitro biological activities. Biol. Pharm. Bull., 2002, 25(1), 58-63.
[http://dx.doi.org/10.1248/bpb.25.58] [PMID: 11824558]
[15]
Choi, K.T. Botanical characteristics, pharmacological effects and medicinal components of Korean Panax ginseng C A Meyer. Acta Pharmacol. Sin., 2008, 29(9), 1109-1118.
[http://dx.doi.org/10.1111/j.1745-7254.2008.00869.x] [PMID: 18718180]
[16]
Bae, S.H.; Park, J.B.; Zheng, Y.F.; Jang, M.J.; Kim, S.O.; Kim, J.Y.; Yoo, Y.H.; Yoon, K.D.; Oh, E.; Bae, S.K. Pharmacokinetics and tissue distribution of ginsenoside Rh2 and Rg3 epimers after oral administration of BST204, a purified ginseng dry extract, in rats. Xenobiotica, 2014, 44(12), 1099-1107.
[http://dx.doi.org/10.3109/00498254.2014.929192] [PMID: 24933530]
[17]
Cheong, J.H.; Kim, H.; Hong, M.J.; Yang, M.H.; Kim, J.W.; Yoo, H.; Yang, H.; Park, J.H.; Sung, S.H.; Kim, H.P.; Kim, J. Stereoisomer-specific anticancer activities of ginsenoside Rg3 and Rh2 in HepG2 cells: disparity in cytotoxicity and autophagy-inducing effects due to 20(S)-epimers. Biol. Pharm. Bull., 2015, 38(1), 102-108.
[http://dx.doi.org/10.1248/bpb.b14-00603] [PMID: 25744465]
[18]
Huang, J.; Peng, K.; Wang, L.; Wen, B.; Zhou, L.; Luo, T.; Su, M.; Li, J.; Luo, Z. Ginsenoside Rh2 inhibits proliferation and induces apoptosis in human leukemia cells via TNF-α signaling pathway. Acta Biochim. Biophys. Sin. (Shanghai), 2016, 48(8), 750-755.
[http://dx.doi.org/10.1093/abbs/gmw049] [PMID: 27177748]
[19]
Chung, K.S.; Cho, S.H.; Shin, J.S.; Kim, D.H.; Choi, J.H.; Choi, S.Y.; Rhee, Y.K.; Hong, H.D.; Lee, K.T. Ginsenoside Rh2 induces cell cycle arrest and differentiation in human leukemia cells by upregulating TGF-β expression. Carcinogenesis, 2013, 34(2), 331-340.
[http://dx.doi.org/10.1093/carcin/bgs341] [PMID: 23125221]
[20]
Liu, Z.H.; Li, J.; Xia, J.; Jiang, R.; Zuo, G.W.; Li, X.P.; Chen, Y.; Xiong, W.; Chen, D.L. Ginsenoside 20(s)-Rh2 as potent natural histone deacetylase inhibitors suppressing the growth of human leukemia cells. Chem. Biol. Interact., 2015, 242, 227-234.
[http://dx.doi.org/10.1016/j.cbi.2015.10.014] [PMID: 26482938]
[21]
Ge, G.; Yan, Y.; Cai, H. Ginsenoside Rh2 Inhibited Proliferation by Inducing ROS Mediated ER Stress Dependent Apoptosis in Lung Cancer Cells. Biol. Pharm. Bull., 2017, 40(12), 2117-2124.
[http://dx.doi.org/10.1248/bpb.b17-00463] [PMID: 28966297]
[22]
Cheng, C.C.; Yang, S.M.; Huang, C.Y.; Chen, J.C.; Chang, W.M.; Hsu, S.L. Molecular mechanisms of ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells. Cancer Chemother. Pharmacol., 2005, 55(6), 531-540.
[http://dx.doi.org/10.1007/s00280-004-0919-6] [PMID: 15739095]
[23]
Zhang, J.; Li, W.; Yuan, Q.; Zhou, J.; Zhang, J.; Cao, Y.; Fu, G.; Hu, W. Transcriptome Analyses of the Anti-Proliferative Effects of 20(S)-Ginsenoside Rh2 on HepG2 Cells. Front. Pharmacol., 2019, 10, 1331.
[http://dx.doi.org/10.3389/fphar.2019.01331] [PMID: 31780945]
[24]
Yang, Z.; Zhao, T.; Liu, H.; Zhang, L. Ginsenoside Rh2 inhibits hepatocellular carcinoma through β-catenin and autophagy. Sci. Rep., 2016, 6, 19383.
[http://dx.doi.org/10.1038/srep19383] [PMID: 26783250]
[25]
Li, Q.; Li, B.; Dong, C.; Wang, Y.; Li, Q. 20(S)-Ginsenoside Rh2 suppresses proliferation and migration of hepatocellular carcinoma cells by targeting EZH2 to regulate CDKN2A-2B gene cluster transcription. Eur. J. Pharmacol., 2017, 815, 173-180.
[http://dx.doi.org/10.1016/j.ejphar.2017.09.023] [PMID: 28928088]
[26]
Shi, Q.; Shi, X.; Zuo, G.; Xiong, W.; Li, H.; Guo, P.; Wang, F.; Chen, Y.; Li, J.; Chen, D.L. Anticancer effect of 20(S)-ginsenoside Rh2 on HepG2 liver carcinoma cells: Activating GSK-3β and degrading β-catenin. Oncol. Rep., 2016, 36(4), 2059-2070.
[http://dx.doi.org/10.3892/or.2016.5033] [PMID: 27573179]
[27]
Kim, M.J.; Yun, H.; Kim, D.H.; Kang, I.; Choe, W.; Kim, S.S.; Ha, J. AMP-activated protein kinase determines apoptotic sensitivity of cancer cells to ginsenoside-Rh2. J. Ginseng Res., 2014, 38(1), 16-21.
[http://dx.doi.org/10.1016/j.jgr.2013.11.010] [PMID: 24558305]
[28]
Chen, F.; Deng, Z.Y.; Zhang, B.; Xiong, Z.X.; Zheng, S.L.; Tan, C.L.; Hu, J.N. Esterification of Ginsenoside Rh2 Enhanced Its Cellular Uptake and Antitumor Activity in Human HepG2 Cells. J. Agric. Food Chem., 2016, 64(1), 253-261.
[http://dx.doi.org/10.1021/acs.jafc.5b05450] [PMID: 26672619]
[29]
Tang, X.P.; Tang, G.D.; Fang, C.Y.; Liang, Z.H.; Zhang, L.Y. Effects of ginsenoside Rh2 on growth and migration of pancreatic cancer cells. World J. Gastroenterol., 2013, 19(10), 1582-1592.
[http://dx.doi.org/10.3748/wjg.v19.i10.1582] [PMID: 23538603]
[30]
Li, B.; Zhao, J.; Wang, C.Z.; Searle, J.; He, T.C.; Yuan, C.S.; Du, W. Ginsenoside Rh2 induces apoptosis and paraptosis-like cell death in colorectal cancer cells through activation of p53. Cancer Lett., 2011, 301(2), 185-192.
[http://dx.doi.org/10.1016/j.canlet.2010.11.015] [PMID: 21194832]
[31]
Han, S.; Jeong, A.J.; Yang, H.; Bin Kang, K.; Lee, H.; Yi, E.H.; Kim, B.H.; Cho, C.H.; Chung, J.W.; Sung, S.H.; Ye, S.K. Ginsenoside 20(S)-Rh2 exerts anti-cancer activity through targeting IL-6-induced JAK2/STAT3 pathway in human colorectal cancer cells. J. Ethnopharmacol., 2016, 194, 83-90.
[http://dx.doi.org/10.1016/j.jep.2016.08.039] [PMID: 27566200]
[32]
Liu, G.W.; Liu, Y.H.; Jiang, G.S.; Ren, W.D. The reversal effect of Ginsenoside Rh2 on drug resistance in human colorectal carcinoma cells and its mechanism. Hum. Cell, 2018, 31(3), 189-198.
[http://dx.doi.org/10.1007/s13577-017-0189-3] [PMID: 29582366]
[33]
Choi, S.; Kim, T.W.; Singh, S.V. Ginsenoside Rh2-mediated G1 phase cell cycle arrest in human breast cancer cells is caused by p15 Ink4B and p27 Kip1-dependent inhibition of cyclin-dependent kinases. Pharm. Res., 2009, 26(10), 2280-2288.
[http://dx.doi.org/10.1007/s11095-009-9944-9] [PMID: 19629651]
[34]
Lee, H.; Lee, S.; Jeong, D.; Kim, S.J. Ginsenoside Rh2 epigenetically regulates cell-mediated immune pathway to inhibit proliferation of MCF-7 breast cancer cells. J. Ginseng Res., 2018, 42(4), 455-462.
[http://dx.doi.org/10.1016/j.jgr.2017.05.003] [PMID: 30337805]
[35]
Choi, S.; Oh, J.Y.; Kim, S.J. Ginsenoside Rh2 induces Bcl-2 family proteins-mediated apoptosis in vitro and in xenografts in vivo models. J. Cell. Biochem., 2011, 112(1), 330-340.
[http://dx.doi.org/10.1002/jcb.22932] [PMID: 21080338]
[36]
Kikuchi, Y.; Sasa, H.; Kita, T.; Hirata, J.; Tode, T.; Nagata, I. Inhibition of human ovarian cancer cell proliferation in vitro by ginsenoside Rh2 and adjuvant effects to cisplatin in vivo. Anticancer Drugs, 1991, 2(1), 63-67.
[http://dx.doi.org/10.1097/00001813-199102000-00009] [PMID: 1958854]
[37]
Shi, X.; Yang, J.; Wei, G. Ginsenoside 20(S)-Rh2 exerts anti- cancer activity through the Akt/GSK3β signaling pathway in human cervical cancer cells. Mol. Med. Rep., 2018, 17(3), 4811-4816.
[http://dx.doi.org/10.3892/mmr.2018.8454] [PMID: 29363731]
[38]
Kim, J.H.; Kim, M.; Yun, S.M.; Lee, S.; No, J.H.; Suh, D.H.; Kim, K.; Kim, Y.B. Ginsenoside Rh2 induces apoptosis and inhibits epithelial-mesenchymal transition in HEC1A and Ishikawa endometrial cancer cells. Biomed. Pharmacother., 2017, 96, 871-876.
[http://dx.doi.org/10.1016/j.biopha.2017.09.033] [PMID: 29078265]
[39]
Liu, J.; Shimizu, K.; Yu, H.; Zhang, C.; Jin, F.; Kondo, R. Stereospecificity of hydroxyl group at C-20 in antiproliferative action of ginsenoside Rh2 on prostate cancer cells. Fitoterapia, 2010, 81(7), 902-905.
[http://dx.doi.org/10.1016/j.fitote.2010.05.020] [PMID: 20554003]
[40]
Zhang, Q.; Hong, B.; Wu, S.; Niu, T. Inhibition of prostatic cancer growth by ginsenoside Rh2. Tumour Biol., 2015, 36(4), 2377-2381.
[http://dx.doi.org/10.1007/s13277-014-2845-5] [PMID: 25416441]
[41]
Oh, M.; Choi, Y.H.; Choi, S.; Chung, H.; Kim, K.; Kim, S.I.; Kim, D.K.; Kim, N.D. Anti-proliferating effects of ginsenoside Rh2 on MCF-7 human breast cancer cells. Int. J. Oncol., 1999, 14(5), 869-875.
[http://dx.doi.org/10.3892/ijo.14.5.869] [PMID: 10200336]
[42]
Carneiro, B.A.; El-Deiry, W.S. Targeting apoptosis in cancer therapy. Nat. Rev. Clin. Oncol., 2020, 17(7), 395-417.
[http://dx.doi.org/10.1038/s41571-020-0341-y] [PMID: 32203277]
[43]
Xia, T.; Wang, J.C.; Xu, W.; Xu, L.H.; Lao, C.H.; Ye, Q.X.; Fang, J.P. 20S-Ginsenoside Rh2 induces apoptosis in human Leukaemia Reh cells through mitochondrial signaling pathways. Biol. Pharm. Bull., 2014, 37(2), 248-254.
[http://dx.doi.org/10.1248/bpb.b13-00667] [PMID: 24492721]
[44]
Liu, X.; Sun, Y.; Yue, L.; Li, S.; Qi, X.; Zhao, H.; Yang, Y.; Zhang, C.; Yu, H. JNK pathway and relative transcriptional factor were involved in ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells. Genet. Mol. Res., 2016, 15(3), 15039003.
[http://dx.doi.org/10.4238/gmr.15039003] [PMID: 27706758]
[45]
Tong-Lin Wu, T.; Tong, Y.C.; Chen, I.H.; Niu, H.S.; Li, Y.; Cheng, J.T. Induction of apoptosis in prostate cancer by ginsenoside Rh2. Oncotarget, 2018, 9(13), 11109-11118.
[http://dx.doi.org/10.18632/oncotarget.24326] [PMID: 29541400]
[46]
Park, E.K.; Lee, E.J.; Lee, S.H.; Koo, K.H.; Sung, J.Y.; Hwang, E.H.; Park, J.H.; Kim, C.W.; Jeong, K.C.; Park, B.K.; Kim, Y.N. Induction of apoptosis by the ginsenoside Rh2 by internalization of lipid rafts and caveolae and inactivation of Akt. Br. J. Pharmacol., 2010, 160(5), 1212-1223.
[http://dx.doi.org/10.1111/j.1476-5381.2010.00768.x] [PMID: 20590613]
[47]
Guo, X.X.; Guo, Q.; Li, Y.; Lee, S.K.; Wei, X.N.; Jin, Y.H. Ginsenoside Rh2 induces human hepatoma cell apoptosisvia bax/bak triggered cytochrome C release and caspase-9/caspase-8 activation. Int. J. Mol. Sci., 2012, 13(12), 15523-15535.
[http://dx.doi.org/10.3390/ijms131215523] [PMID: 23443079]
[48]
Park, H; Kim, S; Kim, J; Kang, H. Reactive oxygen species mediated ginsenoside Rg3- and Rh2-induced apoptosis in hepatoma cells through mitochondrial signaling pathways. Food Chem. Toxicol., 2012, 50(8), 2736-2741.
[49]
Chen, W.; Qiu, Y. Ginsenoside Rh2 Targets EGFR by Up-Regulation of miR-491 to Enhance Anti-tumor Activity in Hepatitis B Virus-Related Hepatocellular Carcinoma. Cell Biochem. Biophys., 2015, 72(2), 325-331.
[http://dx.doi.org/10.1007/s12013-014-0456-9] [PMID: 25561284]
[50]
Fontana, F.; Raimondi, M.; Marzagalli, M.; Di Domizio, A.; Limonta, P. The emerging role of paraptosis in tumor cell biology: Perspectives for cancer prevention and therapy with natural compounds. Biochim. Biophys. Acta Rev. Cancer, 2020, 1873(2), 188338.
[http://dx.doi.org/10.1016/j.bbcan.2020.188338] [PMID: 31904399]
[51]
Wang, Y; Wen, X; Zhang, N; Wang, L; Hao, D; Jiang, X Small- molecule compounds target paraptosis to improve cancer therapy. Biomed. Pharmacother., 2019, 118: 109203.
[http://dx.doi.org/10.1016/j.biopha.2019.109203]
[52]
Lee, D.; Kim, I.Y.; Saha, S.; Choi, K.S. Paraptosis in the anti- cancer arsenal of natural products. Pharmacol. Ther., 2016, 162, 120-133.
[http://dx.doi.org/10.1016/j.pharmthera.2016.01.003] [PMID: 26802901]
[53]
Onorati, A.V.; Dyczynski, M.; Ojha, R.; Amaravadi, R.K. Targeting autophagy in cancer. Cancer, 2018, 124(16), 3307-3318.
[http://dx.doi.org/10.1002/cncr.31335] [PMID: 29671878]
[54]
Deng, S.; Shanmugam, M.K.; Kumar, A.P.; Yap, C.T.; Sethi, G.; Bishayee, A. Targeting autophagy using natural compounds for cancer prevention and therapy. Cancer, 2019, 125(8), 1228-1246.
[http://dx.doi.org/10.1002/cncr.31978] [PMID: 30748003]
[55]
Zhuang, J.; Yin, J.; Xu, C.; Mu, Y.; Lv, S. 20(S)-Ginsenoside Rh2 Induce the Apoptosis and Autophagy in U937 and K562 Cells. Nutrients, 2018, 10(3), 328.
[http://dx.doi.org/10.3390/nu10030328] [PMID: 29518056]
[56]
Li, M.; Zhang, D.; Cheng, J.; Liang, J.; Yu, F. Ginsenoside Rh2 inhibits proliferation but promotes apoptosis and autophagy by down-regulating microRNA-638 in human retinoblastoma cells. Exp. Mol. Pathol., 2019, 108, 17-23.
[http://dx.doi.org/10.1016/j.yexmp.2019.03.004] [PMID: 30853612]
[57]
Yang, D.; Li, X.; Zhang, X. Ginsenoside Rh2 induces DNA damage and autophagy in vestibular schwannoma is dependent of LAMP2 transcriptional suppression. Biochem. Biophys. Res. Commun., 2020, 522(2), 300-307.
[http://dx.doi.org/10.1016/j.bbrc.2019.11.026] [PMID: 31771882]
[58]
Monteiro, J.; Fodde, R. Cancer stemness and metastasis: therapeutic consequences and perspectives. Eur. J. Cancer, 2010, 46(7), 1198-1203.
[http://dx.doi.org/10.1016/j.ejca.2010.02.030] [PMID: 20303259]
[59]
Steeg, P.S. Targeting metastasis. Nat. Rev. Cancer, 2016, 16(4), 201-218.
[http://dx.doi.org/10.1038/nrc.2016.25] [PMID: 27009393]
[60]
Wang, Y.S.; Li, H.; Li, Y.; Zhang, S.; Jin, Y.H. (20S)G-Rh2 Inhibits NF-κB Regulated Epithelial-Mesenchymal Transition by Targeting Annexin A2. Biomolecules, 2020, 10(4), 528.
[http://dx.doi.org/10.3390/biom10040528] [PMID: 32244350]
[61]
Kim, S.Y.; Kim, D.H.; Han, S.J.; Hyun, J.W.; Kim, H.S. Repression of matrix metalloproteinase gene expression by ginsenoside Rh2 in human astroglioma cells. Biochem. Pharmacol., 2007, 74(11), 1642-1651.
[http://dx.doi.org/10.1016/j.bcp.2007.08.015] [PMID: 17880928]
[62]
Li, H.; Huang, N.; Zhu, W.; Wu, J.; Yang, X.; Teng, W.; Tian, J.; Fang, Z.; Luo, Y.; Chen, M.; Li, Y. Modulation the crosstalk between tumor-associated macrophages and non-small cell lung cancer to inhibit tumor migration and invasion by ginsenoside Rh2. BMC Cancer, 2018, 18(1), 579.
[http://dx.doi.org/10.1186/s12885-018-4299-4] [PMID: 29783929]
[63]
Veith, A.P.; Henderson, K.; Spencer, A.; Sligar, A.D.; Baker, A.B. Therapeutic strategies for enhancing angiogenesis in wound healing. Adv. Drug Deliv. Rev., 2019, 146, 97-125.
[http://dx.doi.org/10.1016/j.addr.2018.09.010] [PMID: 30267742]
[64]
Roudsari, L.C.; West, J.L. Studying the influence of angiogenesis in in vitro cancer model systems. Adv. Drug Deliv. Rev., 2016, 97, 250-259.
[http://dx.doi.org/10.1016/j.addr.2015.11.004] [PMID: 26571106]
[65]
Huang, Y.; Huang, H.; Han, Z.; Li, W.; Mai, Z.; Yuan, R. Ginsenoside Rh2 Inhibits Angiogenesis in Prostate Cancer by Targeting CNNM1. J. Nanosci. Nanotechnol., 2019, 19(4), 1942-1950.
[http://dx.doi.org/10.1166/jnn.2019.16404] [PMID: 30486934]
[66]
Ma, J.; Gao, G.; Lu, H.; Fang, D.; Li, L.; Wei, G.; Chen, A.; Yang, Y.; Zhang, H.; Huo, J. Reversal effect of ginsenoside Rh2 on oxaliplatin-resistant colon cancer cells and its mechanism. Exp. Ther. Med., 2019, 18(1), 630-636.
[http://dx.doi.org/10.3892/etm.2019.7604] [PMID: 31258699]
[67]
Taube, J.M.; Galon, J.; Sholl, L.M.; Rodig, S.J.; Cottrell, T.R.; Giraldo, A.G. Implications of the tumor immune microenvironment for staging and therapeutics. Mod. Pathol Inc., 2018, 31(2), 214-234.
[68]
Belli, C.; Trapani, D.; Viale, G.; D’Amico, P.; Duso, B.A.; Della Vigna, P.; Orsi, F.; Curigliano, G. Targeting the microenvironment in solid tumors. Cancer Treat. Rev., 2018, 65, 22-32.
[http://dx.doi.org/10.1016/j.ctrv.2018.02.004] [PMID: 29502037]
[69]
Klemm, F.; Joyce, J.A. Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol., 2015, 25(4), 198-213.
[http://dx.doi.org/10.1016/j.tcb.2014.11.006] [PMID: 25540894]
[70]
Wang, M.; Yan, S.J.; Zhang, H.T.; Li, N.; Liu, T.; Zhang, Y.L.; Li, X.X.; Ma, Q.; Qiu, X.C.; Fan, Q.Y.; Ma, B.A. Ginsenoside Rh2 enhances the antitumor immunological response of a melanoma mice model. Oncol. Lett., 2017, 13(2), 681-685.
[http://dx.doi.org/10.3892/ol.2016.5490] [PMID: 28356946]
[71]
Wang, Z.; Liu, R.; Chen, L.; Wang, H.; Zhou, M.; Wang, Y.; Qin, Y. Pharmacokinetics of Ginsenoside Rh2, the Major Anticancer Ingredient of Ginsenoside H Dripping Pills, in Healthy Subjects. Clin. Pharmacol. Drug Dev., 2020, (0), 1-6.
[http://dx.doi.org/10.1002/cpdd.877] [PMID: 33021081]
[72]
Gu, Y; Wang, GJ; Sun, JG; Jia, YW; Wang, W; Xu, MJ Pharmacokinetic characterization of ginsenoside Rh2, an anticancer nutrient from ginseng, in rats and dogs. Food Chem. Toxicol., 2009, 47(9), 2257-2268.
[http://dx.doi.org/10.1016/j.fct.2009.06.013]
[73]
Yang, Z.; Gao, S.; Wang, J.; Yin, T.; Teng, Y.; Wu, B.; You, M.; Jiang, Z.; Hu, M. Enhancement of oral bioavailability of 20(S)- ginsenoside Rh2 through improved understanding of its absorption and efflux mechanisms. Drug Metab. Dispos., 2011, 39(10), 1866-1872.
[http://dx.doi.org/10.1124/dmd.111.040006] [PMID: 21757611]
[74]
Gu, Y.; Wang, G.J.; Sun, J.G.; Jia, Y.W.; Xie, H.T.; Wang, W. Quantitative determination of ginsenoside Rh2 in rat biosamples by liquid chromatography electrospray ionization mass spectrometry. Anal. Bioanal. Chem., 2006, 386(7-8), 2043-2053.
[http://dx.doi.org/10.1007/s00216-006-0857-8] [PMID: 17082877]
[75]
Wei, G.Q.; Zheng, Y.N.; Li, W.; Liu, W.C.; Lin, T.; Zhang, W.Y.; Chen, H.F.; Zeng, J.Z.; Zhang, X.K.; Chen, Q.C. Structural modification of ginsenoside Rh(2) by fatty acid esterification and its detoxification property in antitumor. Bioorg. Med. Chem. Lett., 2012, 22(2), 1082-1085.
[http://dx.doi.org/10.1016/j.bmcl.2011.11.104] [PMID: 22196118]
[76]
Singh, P.; Kim, Y.J.; Singh, H.; Ahn, S.; Castro-Aceituno, V.; Yang, D.C. In situ preparation of water-soluble ginsenoside Rh2-entrapped bovine serum albumin nanoparticles: in vitro cytocompatibility studies. Int. J. Nanomedicine, 2017, 12, 4073-4084.
[http://dx.doi.org/10.2147/IJN.S125154] [PMID: 28603419]
[77]
Xu, Y.; Li, X.; Gong, W.; Huang, H.B.; Zhu, B.W.; Hu, J.N. Construction of Ginsenoside Nanoparticles with pH/Reduction Dual Response for Enhancement of Their Cytotoxicity Toward HepG2 Cells. J. Agric. Food Chem., 2020, 68(32), 8545-8556.
[http://dx.doi.org/10.1021/acs.jafc.0c03698] [PMID: 32686932]
[78]
Li, S.; Gao, Y.; Ma, W.; Guo, W.; Zhou, G.; Cheng, T.; Liu, Y. EGFR signaling-dependent inhibition of glioblastoma growth by ginsenoside Rh2. Tumour Biol., 2014, 35(6), 5593-5598.
[http://dx.doi.org/10.1007/s13277-014-1739-x] [PMID: 24557544]
[79]
Yuan, D.; Yuan, Q.; Cui, Q.; Liu, C.; Zhou, Z.; Zhao, H.; Dun, Y.; Wang, T.; Zhang, C. Vaccine adjuvant ginsenoside Rg1 enhances immune responses against hepatitis B surface antigen in mice. Can. J. Physiol. Pharmacol., 2016, 94(6), 676-681.
[http://dx.doi.org/10.1139/cjpp-2015-0528] [PMID: 27095502]
[80]
Wang, Y.; Liu, Y.; Zhang, X.Y.; Xu, L.H.; Ouyang, D.Y.; Liu, K.P.; Pan, H.; He, J.; He, X.H. Ginsenoside Rg1 regulates innate immune responses in macrophages through differentially modulating the NF-κB and PI3K/Akt/mTOR pathways. Int. Immunopharmacol., 2014, 23(1), 77-84.
[http://dx.doi.org/10.1016/j.intimp.2014.07.028] [PMID: 25179784]
[81]
Jiang, Z.; Yang, Y.; Yang, Y.; Zhang, Y.; Yue, Z.; Pan, Z.; Ren, X. Ginsenoside Rg3 attenuates cisplatin resistance in lung cancer by downregulating PD-L1 and resuming immune. Biomed. Pharmacother., 2017, 96, 378-383.
[http://dx.doi.org/10.1016/j.biopha.2017.09.129] [PMID: 29031195]
[82]
Chen, Y.; Zhang, Y.; Song, W.; Zhang, Y.; Dong, X.; Tan, M. Ginsenoside Rh2 improves the cisplatin anti-tumor effect in lung adenocarcinoma A549 cells via superoxide and PD-L1. Anticancer. Agents Med. Chem., 2020, 20(4), 495-503.
[http://dx.doi.org/10.2174/1871520619666191209091230] [PMID: 31814556]
[83]
Nguyen, N.H.; Nguyen, C.T.N. Pharmacological effects of ginseng on infectious diseases. Inflammopharmacology, 2019, 27(5), 871-883.
[http://dx.doi.org/10.1007/s10787-019-00630-4] [PMID: 31407196]
[84]
Abdou, Y.; Pandey, M.; Sarma, M.; Shah, S.; Baron, J.; Ernstoff, M.S. Mechanism-based treatment of cancer with immune checkpoint inhibitor therapies. Br. J. Clin. Pharmacol., 2020, 86(9), 1690-1702.
[http://dx.doi.org/10.1111/bcp.14316] [PMID: 32323342]
[85]
Onoi, K.; Chihara, Y.; Uchino, J.; Shimamoto, T.; Morimoto, Y.; Iwasaku, M.; Kaneko, Y.; Yamada, T.; Takayama, K. Immune Checkpoint Inhibitors for Lung Cancer Treatment: A Review. J. Clin. Med., 2020, 9(5), E1362.
[http://dx.doi.org/10.3390/jcm9051362] [PMID: 32384677]
[86]
Xie, J.; Lin, Y. Patient-derived xenograft models for personalized medicine in colorectal cancer. Clin. Exp. Med., 2020, 20(2), 167-172.
[http://dx.doi.org/10.1007/s10238-020-00609-4] [PMID: 32100151]