Journal of Ginseng Research

  • 제42권4호
  • /
  • Pages.562-570
  • /
  • 2018
  • /
  • 1226-8453(pISSN)
  • /
  • 2093-4947(eISSN)
고려인삼학회 (The Korean Society of Ginseng)
권호 표지
DOI QR코드

DOI QR Code

Bioactivity-guided isolation of ginsenosides from Korean Red Ginseng with cytotoxic activity against human lung adenocarcinoma cells

  • Yu, Jae Sik (School of Pharmacy, Sungkyunkwan University) ;
  • Roh, Hyun-Soo (Department of Molecular and Cellular Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Baek, Kwan-Hyuck (Department of Molecular and Cellular Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Lee, Seul (Department of Molecular and Cellular Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Sil (School of Pharmacy, Sungkyunkwan University) ;
  • So, Hae Min (School of Pharmacy, Sungkyunkwan University) ;
  • Moon, Eunjung (Charmzone R&D Center, Charmzone Co. LTD.) ;
  • Pang, Changhyun (School of Chemical Engineering, Sungkyunkwan University) ;
  • Jang, Tae Su (Institute of Green Bio Science & Technology, Seoul National University) ;
  • Kim, Ki Hyun (School of Pharmacy, Sungkyunkwan University)
  • 투고 : 2017.11.26
  • 심사 : 2018.02.08
  • 발행 : 2018.10.15
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Background: Lung cancer is the leading cause of cancer-related death worldwide. In this study, we used a bioactivity-guided isolation technique to identify constituents of Korean Red Ginseng (KRG) with antiproliferative activity against human lung adenocarcinoma cells. Methods: Bioactivity-guided fractionation and preparative/semipreparative HPLC purification were used with LC/MS analysis to separate the bioactive constituents. Cell viability and apoptosis in human lung cancer cell lines (A549, H1264, H1299, and Calu-6) after treatment with KRG extract fractions and constituents thereof were assessed using the water-soluble tetrazolium salt (WST-1) assay and terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, respectively. Caspase activation was assessed by detecting its surrogate marker, cleaved poly adenosine diphosphate (ADP-ribose) polymerase, using an immunoblot assay. The expression and subcellular localization of apoptosis-inducing factor were assessed using immunoblotting and immunofluorescence, respectively. Results and conclusion: Bioactivity-guided fractionation of the KRG extract revealed that its ethyl acetate-soluble fraction exerts significant cytotoxic activity against all human lung cancer cell lines tested by inducing apoptosis. Chemical investigation of the ethyl acetatesoluble fraction led to the isolation of six ginsenosides, including ginsenoside Rb1 (1), ginsenoside Rb2 (2), ginsenoside Rc (3), ginsenoside Rd (4), ginsenoside Rg1 (5), and ginsenoside Rg3 (6). Among the isolated ginsenosides, ginsenoside Rg3 exhibited the most cytotoxic activity against all human lung cancer cell lines examined, with $IC_{50}$ values ranging from $161.1{\mu}M$ to $264.6{\mu}M$. The cytotoxicity of ginsenoside Rg3 was found to be mediated by induction of apoptosis in a caspase-independent manner. These findings provide experimental evidence for a novel biological activity of ginsenoside Rg3 against human lung cancer cells.

키워드

참고문헌

  1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics. CA Cancer J Clin 2010;60:277-300. https://doi.org/10.3322/caac.20073
  2. Baeg IH, So SH. The world ginseng market and the ginseng (Korea). J Ginseng Res. 2013;37:1-7. https://doi.org/10.5142/jgr.2013.37.1
  3. Kim P, Park JH, Kwon KJ, Kim KC, Kim HJ, Lee JM, Kim HY, Han SH, Shin CY. Effects of Korean red ginseng extracts on neural tube defects and impairment of social interaction induced by prenatal exposure to valproic acid. Food Chem Toxicol 2013;51:288-96. https://doi.org/10.1016/j.fct.2012.10.011
  4. Park HM, Kim SJ, Mun AR, Go HK, Kim GB, Kim SZ, Jang SI, Lee SJ, Kim JS, Kang HS. Korean red ginseng and its primary ginsenosides inhibit ethanolinduced oxidative injury by suppression of the MAPK pathway in TIB-73 cells. J Ethnopharmacol 2012;141:1071-6. https://doi.org/10.1016/j.jep.2012.03.038
  5. Paul S, Shin HS, Kang SC. Inhibition of inflammations and macrophage activation by ginsenoside-Re isolated from Korean ginseng (Panax ginseng C.A. Meyer). Food Chem Toxicol 2012;50:1354-61. https://doi.org/10.1016/j.fct.2012.02.035
  6. Lee H, Choi J, Shin SS, Yoon M. Effects of Korean red ginseng (Panax ginseng) on obesity and adipose inflammation in ovariectomized mice. J Ethnopharmacol 2016;178:229-37. https://doi.org/10.1016/j.jep.2015.12.017
  7. Kim DH. Chemical diversity of Panax ginseng, Panax quinquifolium, and Panax notoginseng. J Ginseng Res 2012;36(1):1-15. https://doi.org/10.5142/jgr.2012.36.1.1
  8. Kim WY, Kim JM, Han SB, Lee SK, Kim ND, Park MK, Kim CK, Park JH. Steaming of ginseng at high temperature enhances biological activity. J Nat Prod 2000;63(12):1702-4. https://doi.org/10.1021/np990152b
  9. Kim ND, Kim EM, Kang KW, Cho MK, Choi SY, Kim SG. Ginsenoside Rg3 inhibits phenylephrine-induced vascular contraction through induction of nitric oxide synthase. Br J Pharmacol 2003;140(4):661-70. https://doi.org/10.1038/sj.bjp.0705490
  10. Tian J, Fu F, Geng M, Jiang Y, Yang J, Jiang W, Wang C, Liu K. Neuroprotective effect of 20(S)-ginsenoside Rg3 on cerebral ischemia in rats. Neurosci Lett 2005;374(2):92-7. https://doi.org/10.1016/j.neulet.2004.10.030
  11. Wang CZ, Anderson S, DU W, He TC, Yuan CS. Red ginseng and cancer treatment. Chin J Nat Med 2016;14(1):7-16. https://doi.org/10.3724/SP.J.1009.2016.00007
  12. Bae JK, Kim YJ, Chae HS, Kim DY, Choi HS, Chin YW, Choi YH. Korean red ginseng extract enhances paclitaxel distribution to mammary tumors and its oral bioavailability by P-glycoprotein inhibition. Xenobiotica 2016;17:1-10.
  13. Lee S, Park JM, Jeong M, Han YM, Go EJ, Ko WJ, Cho JY, Kwon CI, Hahm KB. Korean red ginseng ameliorated experimental pancreatitis through the inhibition of hydrogen sulfide in mice. Pancreatology 2016;16:326-36. https://doi.org/10.1016/j.pan.2016.02.012
  14. Jung SY, Kim C, Kim WS, Lee SG, Lee JH, Shim BS, Kim SH, Ahn KS. Korean red ginseng extract enhances the anticancer effects of Imatinib mesylate through abrogation p38 and STAT5 activation in KBM-5 cells. Phytother Res 2015;29:1062-72. https://doi.org/10.1002/ptr.5347
  15. Kim H, Hong MK, Choi H, Moon HS, Lee HJ. Chemopreventive effects of Korean red ginseng extract on rat hepatocarcinogenesis. J Cancer 2015;6:1-8. https://doi.org/10.7150/jca.10353
  16. Jin X, Che DB, Zhang ZH, Yan HM, Jia ZY, Jia XB. Ginseng consumption and risk of cancer: a meta-analysis. J Ginseng Res 2016;40:269-77. https://doi.org/10.1016/j.jgr.2015.08.007
  17. Yun TK, Lee YS, Lee YH, Kim SI, Yun HY. Anticarcinogenic effect of Panax ginseng C.A. Meyer and identification of active compounds. J Korean Med Sci 2001;16(Suppl):S6-18. https://doi.org/10.3346/jkms.2001.16.S.S6
  18. Kang MR, Kim HM, Kang JS, Lee K, Lee SD, Hyun DH, In MJ, Park SK, Kim DC. Lipid-soluble ginseng extract induces apoptosis and G0/G1 cell cycle arrest in NCI-H460 human lung cancer cells. Plant Foods Hum Nutr 2011;66(2):101-6. https://doi.org/10.1007/s11130-011-0232-6
  19. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med 2008;359(13):1367-80. https://doi.org/10.1056/NEJMra0802714
  20. Wang Z, Sun Y. Targeting p53 for novel Anticancer Therapy. Transl Oncol 2010;3(1):1-12. https://doi.org/10.1593/tlo.09250
  21. Lee TK, Roh HS, Yu JS, Baek J, Lee S, Ra M, Kim SY, Baek KH, Kim KH. Pinecone of Pinus koraiensis inducing apoptosis in human lung cancer cells by activating caspase-3 and its chemical constituents. Chem Biodivers 2017;14(4):e1600412. https://doi.org/10.1002/cbdv.201600412
  22. Yu JS, Roh HS, Lee S, Jung K, Baek KH, Kim KH. Antiproliferative effect of Momordica cochinchinensis seeds on human lung cancer cells and isolation of the major constituents. Rev Bras Farmacogn 2017;27(3):329-33. https://doi.org/10.1016/j.bjp.2017.02.002
  23. Baek J, Roh HS, Choi CI, Baek KH, Kim KH. Raphanus sativus sprout causes selective cytotoxic effect on p53-deficient human lung cancer cells in vitro. Nat Prod Commun 2017;12(2):237-40.
  24. Lee TK, Roh HS, Yu JS, Kwon DJ, Kim SY, Baek KH, Kim KH. A novel cytotoxic activity of the fruit of Sorbus commixta against human lung cancer cells and isolation of the major constituents. J Funct Foods 2017;30:1-7. https://doi.org/10.1016/j.jff.2017.01.003
  25. Kim S, So HM, Roh HS, Kim J, Yu JS, Lee S, Seok S, Pang C, Baek KH, Kim KH. Vulpinic acid contributes to the cytotoxicity of Pulveroboletus ravenelii to human cancer cells by inducing apoptosis. RSC Adv 2017;7:35297-304. https://doi.org/10.1039/C7RA05059C
  26. Mitsudomi T, Steinberg SM, Nau MM, Carbone D, Damico D, Bodner S, Oie HK, Linnoila RI, Mulshine JL, Minna JD, et al. p53 gene mutations in non-small-celllung-cancer cell-lines and their correlation with the presence of ras mutations and clinical features. Oncogene 1992;7(1):171-80.
  27. Ramet M, Castren K, Jarvinen K, Pekkala K, Turpeenniemi-Hujanen T, Soini Y, Paakko P, Vahakangas K. p53 protein expression is correlated with benzo[a] pyrene-DNA adducts in carcinoma cell lines. Carcinogenesis 1995;16(9):2117-24. https://doi.org/10.1093/carcin/16.9.2117
  28. Heidebrecht F, Heidebrecht A, Schulz I, Behrens SE, Bader A. Improved semiquantitative Western blot technique with increased quantification range. J Immunol Methods 2009;345(1-2):40-8. https://doi.org/10.1016/j.jim.2009.03.018
  29. Wang CZ, Li XL, Wang QF, Mehendale SR, Fishbein AB, Han AH, Sun S, Yuan CS. The mitochondrial pathway is involved in American ginseng-induced apoptosis of SW- 480 colon cancer cells. Oncol Rep 2009;21:577-84.
  30. Lee JI, Ha YW, Choi TW, Kim HJ, Kim SM, Jang HJ, Choi JH, Choi MH, Chung BC, Sethi G, et al. Cellular uptake of ginsenosides in Korean white ginseng and red ginseng and their apoptotic activities in human breast cancer cells. Planta Med 2011;77(2):133-40. https://doi.org/10.1055/s-0030-1250160
  31. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol 2007;35(4):495-516. https://doi.org/10.1080/01926230701320337
  32. Gebhardt S, Bihler S, Schubert-Zsilavecz M, Riva S, Monti D, Falcone L, Daniele B. Biocatalytic generation of molecular diversity: modification of ginsenoside Rb1 by ${\beta}$-1,4-galactosyltransferase and Candida Antarctica lipase, part 4. Helvetica 2002;85:1943-59.
  33. Su J, Li HZ, Yang CR. Studies on saponin constituents in roots of Panax quinquefolium. Zhangguo Zhang Yao Za Zhi 2003;9:830-3.
  34. Teng R, Ang C, McManus D, Armstrong D, Mau S, Bacic An. Regioselective acylation of ginsenosides by novozyme 435 to generate molecular diversity. Helvetica 2004;87:1860-72.
  35. Ko SR, Choi KJ, Suzki K, Suzuki Y. Enzymatic preparation of ginsenosides Rg2, Rh1, and F1. Chem Pharm Bull 2003;51:404-8. https://doi.org/10.1248/cpb.51.404
  36. Wang W, Zhao Y, Rayburn ER, Hill DL, Wang H, Zhang R. In vitro anti-cancer activity and structureeactivity relationships of natural products isolated from fruits of Panax ginseng. Cancer Chemoth Pharm 2007;59:589-601. https://doi.org/10.1007/s00280-006-0300-z
  37. Lee SY, Kim GT, Roh SH, Song JS, Kim HJ, Hong SS, Kwon SW, Park JH. Proteomic analysis of the anti-cancer effect of 20S-ginsenoside Rg3 in human colon cancer cell lines. Biosci Biotechnol Biochem 2009;73(4):811-6. https://doi.org/10.1271/bbb.80637
  38. Jiang JW, Chen XM, Chen XH, Zheng SS. Ginsenoside Rg3 inhibit hepatocellular carcinoma growth via intrinsic apoptotic pathway. World J Gastroenterol 2011;17(31):3605-13. https://doi.org/10.3748/wjg.v17.i31.3605
  39. Choi YJ, Lee HJ, Kang DW, Han IH, Choi BK, Cho WH. Ginsenoside Rg3 induces apoptosis in the U87MG human glioblastoma cell line through the MEK signaling pathway and reactive oxygen species. Oncol Rep 2013;30(3):1362-70. https://doi.org/10.3892/or.2013.2555
  40. Zhang F, Li M, Wu X, Hu Y, Cao Y, Wang X, Xiang S, Li H, Jiang L, Tan Z, et al. 20(S)-ginsenoside Rg3 promotes senescence and apoptosis in gallbladder cancer cells via the p53 pathway. Drug Des Devel Ther 2015;9:3969-87.
  41. Kim DG, Jung KH, Lee DG, Yoon JH, Choi KS, Kwon SW, Shen HM, Morgan MJ, Hong SS, Kim YS. 20(S)-Ginsenoside Rg3 is a novel inhibitor of autophagy and sensitizes hepatocellular carcinoma to doxorubicin. Oncotarget 2014;5(12):4438-51.
  42. He B, Chen P, Xie Y, Li S, Zhang X, Yang R, Wang G, Shen Z, Wang H. 20(R)-Ginsenoside Rg3 protects SH-SY5Y cells against apoptosis induced by oxygen and glucose deprivation/reperfusion. Bioorg Med Chem Lett 2017 Aug 15;27(16):3867-71.
  43. Kaufmann SH, Desnoyers S, Ottaviano Y, Davidson NE, Poirier GG. Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res 1993;53(17):3976-85.
  44. Gamen S, Anel A, Perez-Galan P, Lasierra P, Johnson D, Pineiro A, Naval J. Doxorubicin treatment activates a Z-VAD-sensitive caspase, which causes deltapsim loss, caspase-9 activity, and apoptosis in Jurkat cells. Exp Cell Res 2000;258(1):223-35. https://doi.org/10.1006/excr.2000.4924
  45. Sevrioukova IF. Apoptosis-inducing factor: structure, function, and redox regulation. Antioxid Redox Signal 2011;14(12):2545-79. https://doi.org/10.1089/ars.2010.3445
  46. Cregan SP, Fortin A, MacLaurin JG, Callaghan SM, Cecconi F, Yu SW, Dawson TM, Dawson VL, Park DS, Kroemer G, et al. Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death. J Cell Biol 2002;158(3):507-17. https://doi.org/10.1083/jcb.200202130
  47. Sun M, Ye Y, Xiao L, Duan X, Zhang Y, Zhang H. Anticancer effects of ginsenoside Rg3 (Review). Int J Mol Med 2017;39(3):507-18. https://doi.org/10.3892/ijmm.2017.2857
  48. Kim BM, Kim DH, Park JH, Na HK, Surh YJ. Ginsenoside Rg3 induces apoptosis of human breast cancer (MDA-MB-231) cells. J Cancer Prev 2013;18(2):177-85. https://doi.org/10.15430/JCP.2013.18.2.177
  49. Cho SH, Chung KS, Choi JH, Kim DH, Lee KT. Compound K, a metabolite of ginseng saponin, induces apoptosis via caspase-8-dependent pathway in HL-60 human leukemia cells. BMC Cancer 2009;9:449. https://doi.org/10.1186/1471-2407-9-449
  50. Law CKM, Kwok HH, Poon PY, Lau CC, Jiang ZH, Tai WCS, Hsiao WWL, Mak NK, Yue PYK, Wong RNS. Ginsenoside compound K induces apoptosis in nasopharyngeal carcinoma cells via activation of apoptosis-inducing factor. Chin Med 2014;9:11. https://doi.org/10.1186/1749-8546-9-11
  51. Park JA, Lee KY, Oh YJ, Kim KW, Lee SK. Activation of caspase-3 protease via a Bcl-2-insensitive pathway during the process of ginsenoside Rh2-induced apoptosis. Cancer Lett 1997;121(1):73-81. https://doi.org/10.1016/S0304-3835(97)00333-9
  52. Qu X, Qu S, Yu X, Xu H, Chen Y, Ma X, Sui D. pseudo-G-Rh2 induces mitochondrial-mediated apoptosis in SGC-7901 human gastric cancer cells. Oncol Rep 2011;26(6):1441-6. https://doi.org/10.3892/or.2011.1442
  53. Joseph B, Ekedahl J, Lewensohn R, Marchetti P, Formstecher P, Zhivotovsky B. Defective caspase-3 relocalization in non-small cell lung carcinoma. Oncogene 2001;20(23):2877-88. https://doi.org/10.1038/sj.onc.1204402
  54. Kim MY. Role of GALNT14 in lung metastasis of breast cancer. BMB Rep 2017;50(5):233-4. https://doi.org/10.5483/BMBRep.2017.50.5.055

피인용 문헌

  1. How Ginsenosides Trigger Apoptosis in Human Lung Adenocarcinoma Cells vol.47, pp.8, 2018, https://doi.org/10.1142/s0192415x19500885
  2. Spectrum-Effect Relationship between UPLC Fingerprints and Antilung Cancer Effect of Si Jun Zi Tang vol.2019, pp.None, 2018, https://doi.org/10.1155/2019/7282681
  3. Modulation of Autophagy for Controlling Immunity vol.8, pp.2, 2018, https://doi.org/10.3390/cells8020138
  4. Betulinic Acid Suppresses Ovarian Cancer Cell Proliferation through Induction of Apoptosis vol.9, pp.7, 2018, https://doi.org/10.3390/biom9070257
  5. Bioactive compounds from the seeds of Amomum tsaoko Crevost et Lemaire, a Chinese spice as inhibitors of sphingosine kinases, SPHK1/2 vol.9, pp.58, 2018, https://doi.org/10.1039/c9ra07988b
  6. Procyanidin B2 3″-O-gallate Isolated from Reynoutria elliptica Prevents Glutamate-Induced HT22 Cell Death by Blocking the Accumulation of Intracellular Reactive Oxygen Species vol.9, pp.9, 2019, https://doi.org/10.3390/biom9090412
  7. Pharmacological effects of ginseng on infectious diseases vol.27, pp.5, 2018, https://doi.org/10.1007/s10787-019-00630-4
  8. Hybrid Polyketides from a Hydractinia-Associated Cladosporium sphaerospermum SW67 and Their Putative Biosynthetic Origin vol.17, pp.11, 2018, https://doi.org/10.3390/md17110606
  9. (3β,16α)-3,16-Dihydroxypregn-5-en-20-one from the Twigs of Euonymus alatus (Thunb.) Sieb. Exerts Anti-Inflammatory Effects in LPS-Stimulated RAW-264.7 Macrophages vol.24, pp.21, 2018, https://doi.org/10.3390/molecules24213848
  10. Suppression of 6-Hydroxydopamine-Induced Oxidative Stress by Hyperoside Via Activation of Nrf2/HO-1 Signaling in Dopaminergic Neurons vol.20, pp.23, 2018, https://doi.org/10.3390/ijms20235832
  11. Anti-adipogenic Effect of β-Carboline Alkaloids from Garlic ( Allium sativum ) vol.8, pp.12, 2018, https://doi.org/10.3390/foods8120673
  12. (–)-Catechin-7- O -β- D -Apiofuranoside Inhibits Hepatic Stellate Cell Activation by Suppressing the STAT3 Signaling Pathway vol.9, pp.1, 2020, https://doi.org/10.3390/cells9010030
  13. Benzyl salicylate from the stems and stem barks of Cornus walteri as a nephroprotective agent against cisplatin-induced apoptotic cell death in LLC-PK1 cells vol.10, pp.10, 2018, https://doi.org/10.1039/c9ra07009e
  14. Absolute Configuration and Corrected NMR Assignment of 17-Hydroxycyclooctatin, a Fused 5-8-5 Tricyclic Diterpene vol.83, pp.2, 2018, https://doi.org/10.1021/acs.jnatprod.9b00837
  15. Inhibitory Effect of 1,5-Dimethyl Citrate from Sea Buckthorn ( Hippophae rhamnoides ) on Lipopolysaccharide-Induced Inflammatory Response in RAW 264.7 Mouse Macrophages vol.9, pp.3, 2018, https://doi.org/10.3390/foods9030269
  16. Megastigmane Derivatives from the Cladodes of Opuntia humifusa and Their Nitric Oxide Inhibitory Activities in Macrophages vol.83, pp.3, 2020, https://doi.org/10.1021/acs.jnatprod.9b01120
  17. Aviculin Isolated from Lespedeza cuneata Induce Apoptosis in Breast Cancer Cells through Mitochondria-Mediated Caspase Activation Pathway vol.25, pp.7, 2018, https://doi.org/10.3390/molecules25071708
  18. Antifungal Phenols from Woodfordia uniflora Collected in Oman vol.83, pp.7, 2018, https://doi.org/10.1021/acs.jnatprod.0c00395
  19. Calvatianone, a Sterol Possessing a 6/5/6/5-Fused Ring System with a Contracted Tetrahydrofuran B-Ring, from the Fruiting Bodies of Calvatia nipponica vol.83, pp.9, 2018, https://doi.org/10.1021/acs.jnatprod.0c00673
  20. Diketoacetonylphenalenone, Derived from Hawaiian Volcanic Soil-Associated Fungus Penicillium herquei FT729, Regulates T Cell Activation via Nuclear Factor-κB and Mitogen-Activated Protein Kina vol.25, pp.22, 2018, https://doi.org/10.3390/molecules25225374
  21. Hepatoprotective Potency of Chrysophanol 8- O -Glucoside from Rheum palmatum L. against Hepatic Fibrosis via Regulation of the STAT3 Signaling Pathway vol.21, pp.23, 2018, https://doi.org/10.3390/ijms21239044
  22. Ent -Peniciherqueinone Suppresses Acetaldehyde-Induced Cytotoxicity and Oxidative Stress by Inducing ALDH and Suppressing MAPK Signaling vol.12, pp.12, 2018, https://doi.org/10.3390/pharmaceutics12121229
  23. The Impact of Gut Microbiome on the Pharmacokinetics of Ginsenosides Rd and Rg3 in Mice after Oral Administration of Red Ginseng vol.49, pp.8, 2021, https://doi.org/10.1142/s0192415x21500890
  24. Metabolite Profile of Cucurbitane-Type Triterpenoids of Bitter Melon (Fruit of Momordica charantia) and Their Inhibitory Activity against Protein Tyrosine Phosphatases Relevant to Insulin Resistance vol.69, pp.6, 2018, https://doi.org/10.1021/acs.jafc.0c06085
  25. Anti-Cancer Effect of Panax Ginseng and Its Metabolites: From Traditional Medicine to Modern Drug Discovery vol.9, pp.8, 2021, https://doi.org/10.3390/pr9081344
  26. Pharmacological properties of ginsenosides in inflammation-derived cancers vol.476, pp.9, 2021, https://doi.org/10.1007/s11010-021-04162-w
  27. The promising therapeutic potentials of ginsenosides mediated through p38 MAPK signaling inhibition vol.7, pp.11, 2018, https://doi.org/10.1016/j.heliyon.2021.e08354