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Planta Med 2013; 79(08): 639-645
DOI: 10.1055/s-0032-1328401
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Antiproliferative and Apoptotic Activities of Triterpenoid Saponins from the Roots of Platycodon grandiflorum and Their Structure-Activity Relationships

Jaemoo Chun
Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Republic of Korea
,
In Jin Ha
Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Republic of Korea
,
Yeong Shik Kim
Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Republic of Korea
› Author Affiliations
Further Information

Publication History

received 08 December 2012
revised 21 February 2013

accepted 28 February 2013

Publication Date:
10 April 2013 (online)

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Abstract

The present study was undertaken to investigate the antiproliferative and apoptotic activities of Platycodon saponins, including platycodin D, 2′′-O-acetylplatycodin D, 3′′-O-acetylplatycodin D, polygalacin D, 2′′-O-acetylpolygalacin D, and 3′′-O-acetylpolygalacin D, isolated from Platycodon grandiflorum, and prosapogenins which lack the C-3 or C-28 sugar residues, obtained from hydrolysis of platycodin D. We also clarified the structure-activity relationships of these molecules to define structural features that are crucial for the biological activity of Platycodon saponins and prosapogenins. The results showed that all Platycodon saponins had antiproliferative effects on the seven types of cancer cell lines tested. In particular, O-acetylation at the C-2 or C-3 position of rhamnose and dehydroxylation at C-24 increase the compoundʼs cytotoxicity, while the loss of sugar residues linked to C-3 or C-28 dramatically reduced cytotoxicity. This cytotoxicity was associated with apoptosis, which was indicated by DNA fragmentation, phosphatidylserine externalization, and the activation of caspases in AGS cells. Furthermore, Platycodon saponins suppressed the phosphorylation of Akt, which resulted in the inhibition of mTOR and NF-κB signaling following the inhibition of their downstream proteins. In conclusion, six Platycodon saponins have antiproliferative activity, and the presence of sugar residues, an O-acetyl group on the rhamnose, and a methyl group at C-4 contributes to their cytotoxicity and apoptotic activity. These findings may be useful in evaluating the structure-activity relationships of Platycodon saponins and modifying them as a potent apoptosis-inducing agent.

Key words

Platycodon grandiflorum - Campanulaceae - triterpenoid saponins - apoptosis - structure-activity relationships
 

  • References

  • 1 Dixon RA, Sumner LW. Legume natural products: understanding and manipulating complex pathways for human and animal health. Plant Physiol 2003; 131: 878-885
    CrossrefPubMedGoogle Scholar
  • 2 Podolak I, Galanty A, Sobolewska D. Saponins as cytotoxic agents: a review. Phytochem Rev 2010; 9: 425-474
    CrossrefPubMedGoogle Scholar
  • 3 Raju J, Mehta R. Cancer chemopreventive and therapeutic effects of diosgenin, a food saponin. Nutr Cancer 2009; 61: 27-35
    CrossrefPubMedGoogle Scholar
  • 4 Wang W, Zhao Y, Rayburn ER, Hill DL, Wang H, Zhang R. In vitro anti-cancer activity and structure-activity relationships of natural products isolated from fruits of Panax ginseng . Cancer Chemother Pharmacol 2007; 59: 589-601
    CrossrefPubMedGoogle Scholar
  • 5 Fatima I, Chandra V, Saxena R, Manohar M, Sanghani Y, Hajela K, Negi MP, Sankhwar PL, Jain SK, Dwivedi A. 2,3-Diaryl-2H-1-benzopyran derivatives interfere with classical and non-classical estrogen receptor signaling pathways, inhibit Akt activation and induce apoptosis in human endometrial cancer cells. Mol Cell Endocrinol 2012; 348: 198-210
    CrossrefPubMedGoogle Scholar
  • 6 Ben Sghaier M, Skandrani I, Nasr N, Franca MG, Chekir-Ghedira L, Ghedira K. Flavonoids and sesquiterpenes from Teucrium ramosissimum promote antiproliferation of human cancer cells and enhance antioxidant activity: a structure-activity relationship study. Environ Toxicol Pharmacol 2011; 32: 336-348
    CrossrefPubMedGoogle Scholar
  • 7 Wang C, Schuller Levis GB, Lee EB, Levis WR, Lee DW, Kim BS, Park SY, Park E. Platycodin D and D3 isolated from the root of Platycodon grandiflorum modulate the production of nitric oxide and secretion of TNF-α in activated RAW 264.7 cells. Int Immunopharmacol 2004; 4: 1039-1049
    CrossrefPubMedGoogle Scholar
  • 8 Lee EJ, Kang M, Kim YS. Platycodin D inhibits lipogenesis through AMPKα-PPARγ2 in 3 T3-L1 cells and modulates fat accumulation in obese mice. Planta Med 2012; 78: 1536-1542
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Chun J, Joo EJ, Kang M, Kim YS. Platycodin D induces anoikis and caspase-mediated apoptosis via p 38 MAPK in AGS human gastric cancer cells. J Cell Biochem 2013; 114: 456-470
    CrossrefPubMedGoogle Scholar
  • 10 Choi YH, Yoo DS, Cha MR, Choi CW, Kim YS, Choi SU, Lee KR, Ryu SY. Antiproliferative effects of saponins from the roots of Platycodon grandiflorum on cultured human tumor cells. J Nat Prod 2010; 73: 1863-1867
    CrossrefPubMedGoogle Scholar
  • 11 Kim R, Tanabe K, Uchida Y, Emi M, Inoue H, Toge T. Current status of the molecular mechanisms of anticancer drug-induced apoptosis. The contribution of molecular-level analysis to cancer chemotherapy. Cancer Chemother Pharmacol 2002; 50: 343-352
    CrossrefPubMedGoogle Scholar
  • 12 Saraste A, Pulkki K. Morphologic and biochemical hallmarks of apoptosis. Cardiovasc Res 2000; 45: 528-537
    CrossrefPubMedGoogle Scholar
  • 13 Tyurina YY, Shvedova AA, Kawai K, Tyurin VA, Kommineni C, Quinn PJ, Schor NF, Fabisiak JP, Kagan VE. Phospholipid signaling in apoptosis: peroxidation and externalization of phosphatidylserine. Toxicology 2000; 148: 93-101
    CrossrefPubMedGoogle Scholar
  • 14 Zhang Y, Jiang Q, Wang N, Dai B, Chen Y, He L. Effects of taspine on proliferation and apoptosis by regulating caspase-3 expression and the ratio of Bax/Bcl-2 in A431 cells. Phytother Res 2011; 25: 357-364
    PubMedGoogle Scholar
  • 15 Ahn KS, Noh EJ, Zhao HL, Jung SH, Kang SS, Kim YS. Inhibition of inducible nitric oxide synthase and cyclooxygenase II by Platycodon grandiflorum saponins via suppression of nuclear factor-κB activation in RAW 264.7 cells. Life Sci 2005; 76: 2315-2328
    CrossrefPubMedGoogle Scholar
  • 16 Ha IJ, Kang M, Na YC, Park Y, Kim YS. Preparative separation of minor saponins from Platycodi Radix by high-speed counter-current chromatography. J Sep Sci 2011; 34: 2559-2565
    CrossrefPubMedGoogle Scholar
  • 17 Ha YW, Na YC, Ha IJ, Kim DH, Kim YS. Liquid chromatography/mass spectrometry-based structural analysis of new platycoside metabolites transformed by human intestinal bacteria. J Pharm Biomed Anal 2010; 51: 202-209
    CrossrefPubMedGoogle Scholar
  • 18 Shin EM, Zhou HY, Guo LY, Kim JA, Lee SH, Merfort I, Kang SS, Kim HS, Kim S, Kim YS. Anti-inflammatory effects of glycyrol isolated from Glycyrrhiza uralensis in LPS-stimulated RAW264.7 macrophages. Int Immunopharmacol 2008; 8: 1524-1532
    CrossrefPubMedGoogle Scholar
  • 19 Yu JS, Kim AK. Platycodin D induces apoptosis in MCF-7 human breast cancer cells. J Med Food 2010; 13: 298-305
    CrossrefPubMedGoogle Scholar
  • 20 Kim MO, Moon DO, Choi YH, Lee JD, Kim ND, Kim GY. Platycodin D induces mitotic arrest in vitro, leading to endoreduplication, inhibition of proliferation and apoptosis in leukemia cells. Int J Cancer 2008; 122: 2674-2681
    CrossrefPubMedGoogle Scholar
  • 21 Sun H, Chen L, Wang J, Wang K, Zhou J. Structure-function relationship of the saponins from the roots of Platycodon grandiflorum for hemolytic and adjuvant activity. Int Immunopharmacol 2011; 11: 2047-2056
    CrossrefPubMedGoogle Scholar
  • 22 Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin 2005; 55: 178-194
    CrossrefPubMedGoogle Scholar
  • 23 Chaudhary LR, Hruska KA. Inhibition of cell survival signal protein kinase B/Akt by curcumin in human prostate cancer cells. J Cell Biochem 2003; 89: 1-5
    CrossrefPubMedGoogle Scholar
  • 24 Xu HL, Yu XF, Qu SC, Qu XR, Jiang YF, Sui da Y. Juglone, from Juglans mandshruica Maxim, inhibits growth and induces apoptosis in human leukemia cell HL-60 through a reactive oxygen species-dependent mechanism. Food Chem Toxicol 2012; 50: 590-596
    PubMedGoogle Scholar
  • 25 Jiang J, Slivova V, Harvey K, Valachovicova T, Sliva D. Ganoderma lucidum suppresses growth of breast cancer cells through the inhibition of Akt/NF-κB signaling. Nutr Cancer 2004; 49: 209-216
    CrossrefPubMedGoogle Scholar
  • 26 Ho HH, Chang CS, Ho WC, Liao SY, Wu CH, Wang CJ. Anti-metastasis effects of gallic acid on gastric cancer cells involves inhibition of NF-κB activity and downregulation of PI3K/AKT/small GTPase signals. Food Chem Toxicol 2010; 48: 2508-2516
    PubMedGoogle Scholar
  • 27 Lin HH, Chen JH, Chou FP, Wang CJ. Protocatechuic acid inhibits cancer cell metastasis involving the down-regulation of Ras/Akt/NF-κB pathway and MMP-2 production by targeting RhoB activation. Br J Pharmacol 2011; 162: 237-254
    CrossrefPubMedGoogle Scholar
  • 28 Park KR, Nam D, Yun HM, Lee SG, Jang HJ, Sethi G, Cho SK, Ahn KS. β-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation. Cancer Lett 2011; 312: 178-188
    CrossrefPubMedGoogle Scholar
  • 29 Maussang D, Langemeijer E, Fitzsimons CP, Stigter-van Walsum M, Dijkman R, Borg MK, Slinger E, Schreiber A, Michel D, Tensen CP, van Dongen GA, Leurs R, Smit MJ. The human cytomegalovirus-encoded chemokine receptor US28 promotes angiogenesis and tumor formation via cyclooxygenase-2. Cancer Res 2009; 69: 2861-2869
    CrossrefPubMedGoogle Scholar