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Effect of sun ginseng potentiation on epirubicin and paclitaxel-induced apoptosis in human cervical cancer cells

  • Lin, Yingjia (Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University) ;
  • Jiang, Dan (Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University) ;
  • Li, Yang (Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University) ;
  • Han, Xinye (Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University) ;
  • Yu, Di (Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University) ;
  • Park, Jeong Hill (College of Pharmacy, Seoul National University) ;
  • Jin, Ying-Hua (Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University)
  • Received : 2014.05.28
  • Accepted : 2014.08.02
  • Published : 2015.01.15

Abstract

Background: Sun ginseng (SG), a specific formulation of quality-controlled red ginseng, contains approximately equal amounts of three major ginsenosides (RK1, Rg3, and Rg5), which reportedly has antitumor-promoting activities in animal models. Methods: MTT assay was used to assess whether SG can potentiate the anticancer activity of epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells; apoptosis status was analyzed by annexin V-FITC and PI and analyzed by flow cytometry; and apoptosis pathway was studied by analysis of caspase-3, -8, and -9 activation, mitochondrial accumulation of Bax and Bak, and cytochrome c release. Results: SG remarkably enhances cancer cell death induced by epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells. Results of the mechanism study highlighted the cooperation between SG and epirubicin or paclitaxel in activating caspase-3 and -9 but not caspase-8. Moreover, SG significantly increased the mitochondrial accumulation of both Bax and Bak triggered by epirubicin or paclitaxel as well as the subsequent release of cytochrome c in the targeted cells. Conclusion: SG significantly potentiated the anticancer activities of epirubicin and paclitaxel in a synergistic manner. These effects were associated with the increased mitochondrial accumulation of both Bax and Bak that led to an enhanced cytochrome c release, caspase-9/-3 activation, and apoptosis. Treating cancer cells by combining epirubicin and paclitaxel with SG may prove to be a novel strategy for enhancing the efficacy of the two drug types.

Keywords

Acknowledgement

Supported by : National Nature Science Foundation of China

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90. https://doi.org/10.3322/caac.20107
  2. Brown JM, Attardi LD. The role of apoptosis in cancer development and treatment response. Nat Rev Cancer 2005;5:231-7. https://doi.org/10.1038/nrc1560
  3. Li Q, Li Y, Wang X, Fang X, He K, Guo X, Zhan Z, Sun C, Jin YH. Co-treatment with ginsenoside Rh2 and betulinic acid synergistically induces apoptosis in human cancer cells in association with enhanced capsase-8 activation, bax translocation, and cytochrome c release. Mol Carcinog 2011;50:760-9. https://doi.org/10.1002/mc.20673
  4. Hengartner MO. The biochemistry of apoptosis. Nature 2000;407:770-6. https://doi.org/10.1038/35037710
  5. Sun C, Guo X-X, Zhu D, Xiao C, Bai X, Li Y, Zhan Z, Li X-L, Song Z-G, Jin Y-H. Apoptosis is induced in cancer cells via the mitochondrial pathway by the novel xylocydine-derived compound JRS-15. Int J Mol Sci 2013;14:850-70. https://doi.org/10.3390/ijms14010850
  6. Chowdhury I, Tharakan B, Bhat GK. Caspases - an update. Comp Biochem Physiol B Biochem Mol Biol 2008;151:10-27. https://doi.org/10.1016/j.cbpb.2008.05.010
  7. Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2002;2:420-30. https://doi.org/10.1038/nrc821
  8. Fulda S, Debatin KM. Sensitization for anticancer drug-induced apoptosis by betulinic acid. Neoplasia 2005;7:162-70. https://doi.org/10.1593/neo.04442
  9. Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 2010;70:440-6. https://doi.org/10.1158/0008-5472.CAN-09-1947
  10. Xiang YZ, Shang HC, Gao XM, Zhang BL. A comparison of the ancient use of ginseng in traditional Chinese medicine with modern pharmacological experiments and clinical trials. Phytother Res 2008;22:851-8. https://doi.org/10.1002/ptr.2384
  11. 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;63:1702-4. https://doi.org/10.1021/np990152b
  12. Lee H, Kim J, Lee SY, Park JH, Hwang GS. Processed panax ginseng, sun ginseng, decreases oxidative damage induced by tert-butyl hydroperoxide via regulation of antioxidant enzyme and anti-apoptotic molecules in HepG2 cells. J Ginseng Res 2012;36:248-55. https://doi.org/10.5142/jgr.2012.36.3.248
  13. Song KC, Chang TS, Lee H, Kim J, Park JH, Hwang GS. Processed Panax ginseng, sun ginseng increases type I collagen by regulating MMP-1 and TIMP-1 expression in human dermal fibroblasts. J Ginseng Res 2012;36:61-7. https://doi.org/10.5142/jgr.2012.36.1.61
  14. Lu P, Su W, Miao ZH, Niu HR, Liu J, Hua QL. Effect and mechanism of ginsenoside Rg3 on postoperative life span of patients with non-small cell lung cancer. Chin J Integr Med 2008;14:33-6. https://doi.org/10.1007/s11655-007-9002-6
  15. Kim HS, Lee EH, Ko SR, Choi KJ, Park JH, Im DS. Effects of ginsenosides Rg3 and Rh2 on the proliferation of prostate cancer cells. Arch Pharm Res 2004;27: 429-35. https://doi.org/10.1007/BF02980085
  16. Luo X, Wang CZ, Chen J, Song WX, Luo J, Tang N, He BC, Kang Q, Wang Y, Du W, et al. Characterization of gene expression regulated by American ginseng and ginsenoside Rg3 in human colorectal cancer cells. Int J Oncol 2008;32:975-83.
  17. Xu TM, Cui MH, Xin Y, Gu LP, Jiang X, Su MM, Wang DD, Wang WJ. Inhibitory effect of ginsenoside Rg3 on ovarian cancer metastasis. Chin Med J (Engl) 2008;121:1394-7.
  18. Liu WK, Xu SX, Che CT. Anti-proliferative effect of ginseng saponins on human prostate cancer cell line. Life Sci 2000;67:1297-306. https://doi.org/10.1016/S0024-3205(00)00720-7
  19. Kim BJ, Nah SY, Jeon JH, So I, Kim SJ. Transient receptor potential melastatin 7 channels are involved in ginsenoside Rg3-induced apoptosis in gastric cancer cells. Basic Clin Pharmacol Toxicol 2011;109:233-9. https://doi.org/10.1111/j.1742-7843.2011.00706.x
  20. Zeng D, Wang J, Kong P, Chang C, Li J, Li J. Ginsenoside Rg3 inhibits HIF-1alpha and VEGF expression in patient with acute leukemia via inhibiting the activation of PI3K/Akt and ERK1/2 pathways. Int J Clin Exp Pathol 2014;7:2172-8.
  21. He BC, Gao JL, Luo X, Luo J, Shen J, Wang L, Zhou Q, Wang YT, Luu HH, Haydon RC, et al. Ginsenoside Rg3 inhibits colorectal tumor growth through the down-regulation of Wnt/ss-catenin signaling. Int J Oncol 2011;38:437-45.
  22. Ko H, Kim YJ, Park JS, Park JH, Yang HO. Autophagy inhibition enhances apoptosis induced by ginsenoside Rk1 in hepatocellular carcinoma cells. Biosci Biotechnol Biochem 2009;73:2183-9. https://doi.org/10.1271/bbb.90250
  23. Kim YJ, Kwon HC, Ko H, Park JH, Kim HY, Yoo JH, Yang HO. Anti-tumor activity of the ginsenoside Rk1 in human hepatocellular carcinoma cells through inhibition of telomerase activity and induction of apoptosis. Biol Pharm Bull 2008;31:826-30. https://doi.org/10.1248/bpb.31.826
  24. Lee KY, Lee YH, Kim SI, Park JH, Lee SK. Ginsenoside-Rg5 suppresses cyclin Edependent protein kinase activity via up-regulating p21Cip/WAF1 and downregulating cyclin E in SK-HEP-1 cells. Anticancer Res 1997;17:1067-72.
  25. Khasraw M, Bell R, Dang C. Epirubicin: Is it like doxorubicin in breast cancer? A clinical review. Breast 2012;21:142-9. https://doi.org/10.1016/j.breast.2011.12.012
  26. Men Y, Wang XX, Li RJ, Zhang Y, Tian W, Yao HJ, Ju RJ, Ying X, Zhou J, Li N, et al. The efficacy of mitochondrial targeting antiresistant epirubicin liposomes in treating resistant leukemia in animals. Int J Nanomedicine 2011;6:3125-37.
  27. Rabelo E, De Angelis K, Bock P, Fernandes TG, Cervo F, Klein AB, Clausell N, Irigoyen MC. Baroreflex sensitivity and oxidative stress in adriamycin-induced heart failure. Hypertension 2001;38:576-80. https://doi.org/10.1161/hy09t1.096185
  28. Safra T, Menczer J, Bernstein RM, Shpigel S, Matcejevsky D, Inbar MJ, Golan A, Grisaru D, Levy T. Combined weekly carboplatin and paclitaxel as primary treatment of advanced epithelial ovarian carcinoma. Gynecol Oncol 2009;114: 215-8. https://doi.org/10.1016/j.ygyno.2009.04.008
  29. Chang YF, Li LL, Wu CW, Liu TY, Lui WY, P'Eng FK, Chi CW. Paclitaxel-induced apoptosis in human gastric carcinoma cell lines. Cancer 1996;77:14-8. https://doi.org/10.1002/(SICI)1097-0142(19960101)77:1<14::AID-CNCR4>3.0.CO;2-N
  30. Yen WC, Wientjes MG, Au JL. Differential effect of taxol in rat primary and metastatic prostate tumors: site-dependent pharmacodynamics. Pharm Res 1996;13:1305-12. https://doi.org/10.1023/A:1016053412582
  31. Wilson CR, Sauer J, Hooser SB. Taxines: a review of the mechanism and toxicity of yew (Taxus spp.) alkaloids. Toxicon 2001;39:175-85. https://doi.org/10.1016/S0041-0101(00)00146-X
  32. Wang TH, Wang HS, Soong YK. Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. Cancer 2000;88:2619-28. https://doi.org/10.1002/1097-0142(20000601)88:11<2619::AID-CNCR26>3.0.CO;2-J
  33. Huisman C, Ferreira CG, Broker LE, Rodriguez JA, Smit EF, Postmus PE, Kruyt FA, Giaccone G. Paclitaxel triggers cell death primarily via caspase-independent routes in the non-small cell lung cancer cell line NCI-H460. Clin Cancer Res 2002;8:596-606.
  34. Park SJ, Wu CH, Gordon JD, Zhong X, Emami A, Safa AR. Taxol induces caspase- 10-dependent apoptosis. J Biol Chem 2004;279:51057-67. https://doi.org/10.1074/jbc.M406543200
  35. Scripture CD, Figg WD, Sparreboom A. Peripheral neuropathy induced by paclitaxel: recent insights and future perspectives. Curr Neuropharmacol 2006;4:165-72. https://doi.org/10.2174/157015906776359568
  36. Itoh Y, Sendo T, Hirakawa T, Goromaru T, Takasaki S, Yahata H, Nakano H, Oishi R. Role of sensory nerve peptides rather than mast cell histamine in paclitaxel hypersensitivity. Am J Respir Crit Care Med 2004;169:113-9. https://doi.org/10.1164/rccm.200307-901OC
  37. Ajani JA, Dodd LG, Daugherty K, Warkentin D, Ilson DH. Taxol-induced softtissue injury secondary to extravasation: characterization by histopathology and clinical course. J Natl Cancer Inst 1994;86:51-3. https://doi.org/10.1093/jnci/86.1.51
  38. Kang KS, Yamabe N, Kim HY, Yokozawa T. Effect of sun ginseng methanol extract on lipopolysaccharide-induced liver injury in rats. Phytomedicine 2007;14:840-5. https://doi.org/10.1016/j.phymed.2007.01.002
  39. Zhan Z, He K, Zhu D, Jiang D, Huang YH, Li Y, Sun C, Jin YH. Phosphorylation of Rad9 at serine 328 by cyclin A-Cdk2 triggers apoptosis via interfering Bcl-xL. PLoS One 2012;7:e44923. https://doi.org/10.1371/journal.pone.0044923
  40. Li Y, He K, Huang Y, Zheng D, Gao C, Cui L, Jin YH. Betulin induces mitochondrial cytochrome c release associated apoptosis in human cancer cells. Mol Carcinog 2010;49:630-40.
  41. Chipuk JE, Green DR. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends In Cell Biology 2008;18:157-64. https://doi.org/10.1016/j.tcb.2008.01.007

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