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Protective effect of ginsenoside Rh3 against anticancer drug-induced apoptosis in LLC-PK1 kidney cells

  • Lee, Hye Lim (College of Korean Medicine, Gachon University) ;
  • Kang, Ki Sung (College of Korean Medicine, Gachon University)
  • Received : 2016.09.29
  • Accepted : 2017.01.18
  • Published : 2017.04.15

Abstract

Background: Ginsenosides are active components of Panax ginseng that exert various health benefits including kidney protection effect. The medicinal activity of ginsenosides can be enhanced by modulating their stereospecificity by heat processing. Ginsenosides Rk2 and Rh3 represent positional isomers of the double bond at C-20(21) or C-20(22). Methods: The present study investigated the kidney-protective effects of ginsenosides Rk2 and Rh3 against cisplatin, a platinum based anticancer drug, induced apoptotic damage in renal proximal LLC-PK1 cells. Results: As a result, ginsenoside Rh3 shows a stronger protective effect than that shown by Rk2. Cisplatin-induced elevated protein levels of phosphorylated c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), p38, and cleaved caspase-3 decreased after cotreatment with ginsenoside Rh3. The increase in the percentage of apoptotic LLC-PK1 cells induced by cisplatin treatment also significantly reduced after cotreatment with ginsenoside Rh3. Conclusion: These results demonstrate that inhibition of the JNK and ERK mitogen-activated protein kinase signaling cascade plays a critical role in mediating the renoprotective effect of ginsenoside Rh3.

Keywords

References

  1. Kang KS, Kim HY, Yamabe N, Yokozawa T. Stereospecificity in hydroxyl radical scavenging activities of four ginsenosides produced by heat processing. Bioorg Med Chem Lett 2006;16:5028-31. https://doi.org/10.1016/j.bmcl.2006.07.071
  2. Lee CH, Kim JH. A review on the medicinal potentials of ginseng and ginsenosides on cardiovascular diseases. J Ginseng Res 2014;38:161-6. https://doi.org/10.1016/j.jgr.2014.03.001
  3. Kang KS, Ham J, Kim YJ, Park JH, Cho EJ, Yamabe N. Heat-processed Panax ginseng and diabetic renal damage: active components and action mechanism. J Ginseng Res 2013;37:379-88. https://doi.org/10.5142/jgr.2013.37.379
  4. Arany I, Safirstein RL. Cisplatin nephrotoxicity. Semin Nephrol 2003;23:460-4. https://doi.org/10.1016/S0270-9295(03)00089-5
  5. Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 2008;73:994-1007. https://doi.org/10.1038/sj.ki.5002786
  6. Kim T, Kim YJ, Han IH, Lee D, Ham J, Kang KS, et al. The synthesis of sulforaphane analogues and their protection effect against cisplatin induced cytotoxicity in kidney cells. Bioorg Med Chem Lett 2015;25:62-6. https://doi.org/10.1016/j.bmcl.2014.11.014
  7. Lee D, Kim KH, Moon SW, Lee H, Kang KS, Lee JW. Synthesis and biological evaluation of chalcone analogues as protective agents against cisplatininduced cytotoxicity in kidney cells. Bioorg Med Chem Lett 2015;25:1929-32. https://doi.org/10.1016/j.bmcl.2015.03.026
  8. Lee S, Jung K, Lee D, Lee SR, Lee KR, Kang KS, et al. Protective effect and mechanism of action of lupane triterpenes from Cornus walteri in cisplatininduced nephrotoxicity. Bioorg Med Chem Lett 2015;25:5613-8. https://doi.org/10.1016/j.bmcl.2015.10.035
  9. Park JY, Lee D, Jang HJ, Jang DS, Kwon HC, Kim KH, et al. Protective effect of Artemisia asiatica extract and its active compound eupatilin against cisplatininduced renal damage. Evid Based Complement Alternat Med 2015;2015:483980.
  10. Bakir S, Yazgan UC, Ibiloglu I, Elbey B, Kizil M, Kelle M. The protective effect of pomegranate extract against cisplatin toxicity in rat liver and kidney tissue. Arch Physiol Biochem 2015;121:152-6. https://doi.org/10.3109/13813455.2015.1068336
  11. Jin J, Li M, Zhao Z, Sun X, Li J, Wang W, et al. Protective effect of Wuzhi tablet (Schisandra sphenanthera extract) against cisplatin-induced nephrotoxicity via Nrf2-mediated defense response. Phytomedicine 2015;22:528-35. https://doi.org/10.1016/j.phymed.2015.03.003
  12. Kim TW, Kim YJ, Park SR, Seo CS, Ha H, Shin HK, et al. Chrysanthemum indicum attenuates cisplatin-induced nephrotoxicity both in vivo and in vitro. Nat Prod Commun 2015;10:397-402.
  13. Kim EJ, Jung IH, Van Le TK, Jeong JJ, Kim NJ, Kim DH. Ginsenosides Rg5 and Rh3 protect scopolamine-induced memory deficits in mice. J Ethnopharmacol 2013;146:294-9. https://doi.org/10.1016/j.jep.2012.12.047
  14. Park IH, Kim NY, Han SB, Kim JM, Kwon SW, Kim HJ, et al. Three new dammarane glycosides from heat processed ginseng. Arch Pharm Res 2002;25:428-32. https://doi.org/10.1007/BF02976595
  15. Safi W, Kuehnl A, Nussler A, Eckstein HH, Pelisek J. Differentiation of human CD14+ monocytes: an experimental investigation of the optimal culture medium and evidence of a lack of differentiation along the endothelial line. Exp Mol Med 2016;48:e227. https://doi.org/10.1038/emm.2016.11
  16. Cao Z, Dou C, Li J, Tang X, Xiang J, Zhao C, et al. Cordycepin inhibits chondrocyte hypertrophy of mesenchymal stem cells through PI3K/Bapx1 and Notch signaling pathway. BMB Rep 2016;49:548-53. https://doi.org/10.5483/BMBRep.2016.49.10.071
  17. Han MS, Han IH, Lee D, An JM, Kim SN, Shin MS, Yamabe N, Hwang GS, Yoo HH, Choi SJ, et al. Beneficial effects of fermented black ginseng and its ginsenoside 20(S)-Rg3 against cisplatin-induced nephrotoxicity in LLC-PK1 cells. J Ginseng Res 2016;40:135-40. https://doi.org/10.1016/j.jgr.2015.06.006
  18. Kim YJ, Choi WI, Jeon BN, Choi KC, Kim K, Kim TJ, et al. Stereospecific effects of ginsenoside 20-Rg3 inhibits $TGF-{\beta}1-induced$ epithelial-mesenchymal transition and suppresses lung cancer migration, invasion, and anoikis resistance. Toxicology 2014;322:23-33. https://doi.org/10.1016/j.tox.2014.04.002
  19. Park EH, Kim YJ, Yamabe N, Park SH, Kim HK, Jang HJ, et al. Stereospecific anticancer effects of ginsenoside Rg3 epimers isolated from heat-processed American ginseng on human gastric cancer cell. J Ginseng Res 2014;38:22-7. https://doi.org/10.1016/j.jgr.2013.11.007
  20. Park JY, Choi P, Kim HK, Kang KS, Ham J. Increase in apoptotic effect of Panax ginseng by microwave processing in human prostate cancer cells: in vitro and in vivo studies. J Ginseng Res 2016;40:62-7. https://doi.org/10.1016/j.jgr.2015.04.007
  21. Seo JW, Yang EJ, Kim SH, Choi IH. An inhibitory alternative splice isoform of Toll-like receptor 3 is induced by type I interferons in human astrocyte cell lines. BMB Rep 2015;48:696-701. https://doi.org/10.5483/BMBRep.2015.48.12.106
  22. Luo H, Wang J, Qiao C, Ma N, Liu D, Zhang W. Pycnogenol attenuates atherosclerosis by regulating lipid metabolism through the $TLR4-NF-{\kappa}B$ pathway. Exp Mol Med 2015;47:e191. https://doi.org/10.1038/emm.2015.74
  23. Lee YY, Park JS, Lee EJ, Lee SY, Kim DH, Kang JL, et al. Anti-inflammatory mechanism of ginseng saponin metabolite Rh3 in lipopolysaccharidestimulated microglia: critical role of 5'-adenosine monophosphate-activated protein kinase signaling pathway. J Agric Food Chem 2015;63:3472-80. https://doi.org/10.1021/jf506110y
  24. Cowan KJ, Storey KB. Mitogen-activated protein kinases: new signaling pathways functioning in cellular responses to environmental stress. J Exp Biol 2003;206:1107-15. https://doi.org/10.1242/jeb.00220
  25. Wang D, Lippard SJ. Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 2005;4:307-20. https://doi.org/10.1038/nrd1691
  26. Quan K, Liu Q, Wan JY, Zhao YJ, Guo RZ, Alolga RN, et al. Rapid preparation of rare ginsenosides by acid transformation and their structure-activity relationships against cancer cells. Sci Rep 2015;5:8598. https://doi.org/10.1038/srep08598

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