Download PDF
Planta Med 2016; 82(01/02): 171-179
DOI: 10.1055/s-0035-1557900
Analytical Studies
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Bioassay Guided Fractionation Identified Hederagenin as a Major Cytotoxic Agent from Cyclocarya paliurus Leaves

Ying Gao   *
1   Tennessee Center for Botanical Medicine Research and the Department of Biology, Middle Tennessee State University, Murfreesboro, TN, USA
,
Chunnian He   *
2   Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Hai Dian District, Beijing, P. R. China
,
Wu Bi
2   Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Hai Dian District, Beijing, P. R. China
,
Guofan Wu
3   College of Life Science, Northwest Normal University, Lanzhou, Gansu Province, P. R. China
,
Elliot Altman
1   Tennessee Center for Botanical Medicine Research and the Department of Biology, Middle Tennessee State University, Murfreesboro, TN, USA
› Author Affiliations
Further Information

Publication History

received 05 May 2015
revised 13 July 2015

accepted 27 July 2015

Publication Date:
21 September 2015 (online)

    Permissions and Reprints

Abstract

An ethanol extract prepared from the leaves of Cyclocarya paliurus, also known as sweet tea, which is one of the most popular teas utilized in traditional Chinese medicine, exhibited significant cytotoxicity against human lung and breast cancer cells. Using a bioassay-guided fractionation, we purified a pentacyclic triterpenoid, hederagenin, which exhibited superior and selective cytotoxicity against human breast and lung cancer cells. Evaluation of the structure-activity relationship between hederagenin and seven other pentacyclic triterpenoids revealed that the C3 hydroxyl group, the C17 carboxyl group and the Δ 12,13 double bond could be important active groups for the bioactivity of pentacyclic triterpenoids, whereas introduction of a hydroxyl group at C2 or C23 might reduce their bioactivity. We also investigated the cytotoxic activity of hedeargenin and demonstrated that it induces apoptosis, increases the cell membrane permeability, reduces the mitochondria potential, and suppresses NF-κB activation.

Key words

Cyclocarya paliurus - Juglandaceae - hederagenin - pentacyclic triterpenoids - cytotoxicity - NF-κB activation

* These authors contributed equally to this work.


Supporting Information

 

  • References

  • 1 American Cancer Society. Cancer Facts & Figures. Atlanta: American Cancer Society; 2014
    Google Scholar
  • 2 He CN, Peng Y, Xiao W, Xu LJ, Xiao PG. The history and research status of the “Magic Tea” Cyclocarya paliurus . Mod Chin Med 2012; 14: 62-68
    PubMedGoogle Scholar
  • 3 “Chinese Herb” Editors of State Administration of Traditional Chinese Medicine. Chinese Herb. Shanghai: Shanghai Scientific and Technical Publishers; 1999: 370-371
    Google Scholar
  • 4 China National Corp. of Traditional & Herbal Medicine. Records of traditional Chinese medicine resources. Beijing: Science Press; 1994: 159-160
    Google Scholar
  • 5 Wang Q, Jiang C, Fang S, Wang J, Ji Y, Shang X, Ni Y, Yin Z, Zhang J. Antihyperglycemic, antihyperlipidemic and antioxidant effects of ethanol and aqueous extracts of Cyclocarya paliurus leaves in type 2 diabetic rats. J Ethnopharmacol 2013; 150: 1119-1127
    CrossrefPubMedGoogle Scholar
  • 6 Li S, Li J, Guan XL, Li J, Deng SP, Li LQ, Tang MT, Huang JG, Chen ZZ, Yang RY. Hypoglycemic effects and constituents of the barks of Cyclocarya paliurus and their inhibiting activities to glucosidase and glycogen phosphorylase. Fitoterapia 2011; 82: 1081-1085
    CrossrefPubMedGoogle Scholar
  • 7 Jiang C, Yao N, Wang Q, Zhang J, Sun Y, Xiao N, Liu K, Huang F, Fang S, Shang X, Liu B, Ni Y, Yin Z, Zhang J. Cyclocarya paliurus extract modulates adipokine expression and improves insulin sensitivity by inhibition of inflammation in mice. J Ethnopharmacol 2014; 153: 344-351
    CrossrefPubMedGoogle Scholar
  • 8 Kurihara H, Fukami H, Kusumoto A, Toyoda Y, Shibata H, Matsui Y, Asami S, Tanaka T. Hypoglycemic action of Cyclocarya paliurus (Batal.) Iljinskaja in normal and diabetic mice. Biosci Biotechnol Biochem 2003; 67: 877-880
    CrossrefPubMedGoogle Scholar
  • 9 Jiang ZY, Zhang XM, Zhou J, Qiu SX, Chen JJ. Two new triterpenoid glycosides from Cyclocarya paliurus . J Asian Nat Prod Res 2006; 8: 93-98
    CrossrefPubMedGoogle Scholar
  • 10 Li J, Lu Y, Su X, Li F, She Z, He X, Lin Y. A norsesquiterpene lactone and a benzoic acid derivative from the leaves of Cyclocarya paliurus and their glucosidase and glycogen phosphorylase inhibiting activities. Planta Med 2008; 74: 287-289
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Zhang J, Shen Q, Lu JC, Li JY, Liu WY, Yang JJ, Li J, Xiao K. Phenolic compounds from the leaves of Cyclocarya paliurus (Batal.) Ijinskaja and their inhibitory activity against PTP1B. Food Chem 2009; 119: 1491-1496
    PubMedGoogle Scholar
  • 12 Xie JH, Xie MY, Nie SP, Shen MY, Wang YX, Li C. Isolation, chemical composition and antioxidant activities of a water-soluble polysaccharide from Cyclocarya paliurus (Batal.) Iljinskaja. Food Chem 2010; 119: 1626-1632
    CrossrefPubMedGoogle Scholar
  • 13 Xie MY, Li L, Nie SP, Wang XR, Lee FSC. Determination of speciation of elements related to blood sugar in bioactive extracts from Cyclocarya paliurus leaves by FIA–ICP–MS. Eur Food Res Technol 2006; 223: 202-209
    CrossrefPubMedGoogle Scholar
  • 14 Shi XL, Shangguan XC, Wang WJ, Shen YG, Jiang Y, Yin ZP. Antihyperglycemic effect of Cyclocarya paliurus polysaccharides in alloxan induced diabetic mice. J Nutr 2009; 31: 263-266
    PubMedGoogle Scholar
  • 15 Shangguan X, Chen W, Jiang Y, Wu S. Hypoglycemic effect of Cyclocarya paliurus (batal.) ijinskaja polysaccharide on diabetic and normal mice. Food Sci Technol 2010; 35: 82-84
    PubMedGoogle Scholar
  • 16 Huang DF, Nie SP, Xie JH, Han C, Xie MY. Effect of Cyclocarya paliurus (Batal) Iljinskaja polysaccharides on the surface molecule expression level of dendritic cells. Nat Prod Res Dev 2009; 21: 771-775
    PubMedGoogle Scholar
  • 17 Xie JH, Shen MY, Xie MY, Nie SP, Chen Y, Li C, Huang DF, Wang YX. Ultrasonic-assisted extraction, antimicrobial and antioxidant activities of Cyclocarya paliurus (Batal.) Iljinskaja polysaccharides. Carbohydr Polym 2012; 89: 177-184
    CrossrefPubMedGoogle Scholar
  • 18 Han C, Nie SP, Huang DF, Chen YQ, Xie JH, Xie MY. Effects of polysaccharides from Cyclocarya paliurus (Batal.) Iljinskjk on growth of MGC-803 Cells. Nat Prod Res Dev 2009; 21: 952-955
    PubMedGoogle Scholar
  • 19 Xie JH, Liu X, Shen MY, Nie SP, Zhang H, Li C, Gong DM, Xie MY. Purification, physicochemical characterisation and anticancer activity of a polysaccharide from Cyclocarya paliurus leaves. Food Chem 2013; 136: 1453-1460
    CrossrefPubMedGoogle Scholar
  • 20 Min FF, Wan YJ, Nie SP, Xie MY. Study on colon health benefit of polysaccharide from Cyclocarya paliurus leaves in vivo . J Funct Foods 2014; 11: 203-209
    CrossrefPubMedGoogle Scholar
  • 21 Wright ME, Byrd J, He C, Dunlap N. Synthesis of cyclocaric acid A and comparison to material from Cyclocarya paliurus . J Nat Prod 2014; 77: 2566-2569
    CrossrefPubMedGoogle Scholar
  • 22 Bi W, He CN, Peng Y, Liu YZ, Xiao PG. Chemical constituents from the petroleum ether fraction of ku-jin tea. Mod Chin Med 2015; 17: 544-547
    PubMedGoogle Scholar
  • 23 Shu RG, Liu YF, Chen J, Shu JC. Studies on triterpenoids from Cyclocarya paliurus . J Chin Med Mater 2005; 28: 558-559
    PubMedGoogle Scholar
  • 24 Hu XY, Luo YG, Chen R, Zhou L. Study advances on taraxerane triterpenoids and their spectroscopic characteristic. Nat Prod Res Dev 2007; 19: 170-178
    PubMedGoogle Scholar
  • 25 Xie MY, Li L. Review in studies on chemical constituents and bioactivities of Cyclocarya paliurus . Chin Tradit Herb Drugs 2001; 32: 365-366
    PubMedGoogle Scholar
  • 26 Liubao XZ, Wang RP, Zou X, Zhou JY. Effect of hederagenin on biological behaviors including proliferation, adhesion, invasion and migration capabilities of human gastric cancer cell line. Chin J Experi Trad Med Formul, 2013; 4: 212-215
    PubMedGoogle Scholar
  • 27 Connolly JD, Hill RA. Triterpenoids. Nat Prod Rep 2010; 27: 79-132
    CrossrefPubMedGoogle Scholar
  • 28 Laszczyk MN. Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy. Planta Med 2009; 75: 1549-1560
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Salvador JA, Leal AS, Alho DP, Gonçalves BM, Valdeira AS, Mendes VI, Jing Y. Highlights of pentacyclic triterpenoids in the cancer settings. In: Rahman A, editor Studies in natural products chemistry. Oxford: Elsevier; 2014: 33-73
    Google Scholar
  • 30 Gauthier C, Legault J, Girard-Lalancette K, Mshvildadze V, Pichette A. Haemolytic activity, cytotoxicity and membrane cell permeabilization of semi-synthetic and natural lupane- and oleanane-type saponins. Bioorg Med Chem 2009; 17: 2002-2008
    CrossrefPubMedGoogle Scholar
  • 31 Zhang LJ, Cheng JJ, Liao CC, Cheng HL, Huang HT, Kuo LMY, Kuo YH. Triterpene acids from Euscaphis japonica and assessment of their cytotoxic and anti-NO activities. Planta Med 2012; 78: 1584-1590
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Zhou JY, Li Y, Zou X, Wu J, Gu JF, Yuan JR, Zhao BJ, Feng L, Jia XB, Wang RP. Hederagenin from the leaves of ivy (Hedera helix L.) induces apoptosis in human LoVo colon cells through the mitochondrial pathway. BMC Complement Altern Med 2014; 14: 412
    CrossrefPubMedGoogle Scholar
  • 33 Wang J, Zhao XZ, Qi Q, Tao L, Zhao Q, Mu R, Gu HY, Wang M, Feng X, Guo QL. Macranthoside B, a hederagenin saponin extracted from Lonicera macranthoides and its anti-tumor activities in vitro and in vivo . Food Chem Toxicol 2009; 47: 1716-1721
    CrossrefPubMedGoogle Scholar
  • 34 Shanmugam MK, Nguyen AH, Kumar AP, Tan BK, Sethi G. Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: potential role in prevention and therapy of cancer. Cancer Lett 2012; 320: 158-170
    CrossrefPubMedGoogle Scholar
  • 35 Yao XY, Li G, Bai Q, Xu H, Lv CT. Taraxerol inhibits LPS-induced inflammatory responses through suppression of TAK1 and Akt activation. Int Immunopharmacol 2013; 15: 316-324
    CrossrefPubMedGoogle Scholar
  • 36 Zhang Y, Xu XM, Zhang M, Qu D, Niu HY, Bai X, Kan L, He P. Effects of tubeimoside 1 on the proliferation and apoptosis of BGC823 gastric cancer cells in vitro. Oncol Lett 2013; 5: 801-804
    PubMedGoogle Scholar
  • 37 Tang XL, Yang XY, Jung HJ, Kim SY, Jung SY, Choi DY, Park WC, Park H. Asiatic acid induces colon cancer cell growth inhibition and apoptosis through mitochondrial death cascade. Biol Pharm Bull 2009; 32: 1399-1405
    CrossrefPubMedGoogle Scholar
  • 38 Meng Y, Zhao L, Wang Z, Lu M, Liu D. Structure-activity relationship of pentacyclic triterpenes. Chin J New Drugs 2004; 13: 1098-1102
    PubMedGoogle Scholar
  • 39 Ding L, Hou Q, Xu FC, Zhang Q, Wang H, Liu GA. The effect of hederagenin, a triterpnoid from Patrinia heterophylla Bunge. on the proliferation inhibition, cell cycle arrest and apoptosis of human promyelocytic leukemia HL-60 cells. J Northwest Norm Univ (Nat Sci) 2009; 45: 88-93
    PubMedGoogle Scholar
  • 40 Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 2010; 11: 621-632
    CrossrefPubMedGoogle Scholar
  • 41 Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM. Suppression of TNF-α-induced apoptosis by NF-κB. Science 1996; 274: 787-789
    CrossrefPubMedGoogle Scholar