Skip to main content
SpringerLink
Log in

Effects of sesquiterpene, flavonoid and coumarin types of compounds from Artemisia annua L. on production of mediators of angiogenesis

  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Background

In addition to recognized antimalarial effects, Artemisia annua L. (Qinghao) possesses anticancer properties. The underlying mechanisms of this activity are unknown. The aim of our experiments was to investigate the effects of distinct types of compounds isolated from A. annua on the immune-activated production of major mediators of angiogenesis playing a crucial role in growth of tumors and formation of metastasis.

Methods

Included in the study were the sesquiterpene lactones artemisinin and its biogenetic precursors arteannuin B and artemisinic acid. The semi-synthetic analogue dihydroartemisinin was used for comparative purposes. The flavonoids were represented by casticin and chrysosplenol D, the coumarin type of compounds by 4-methylesculetin. Their effects on the lipopolysaccharide (LPS)-induced in vitro production of nitric oxide (NO) were analyzed in rat peritoneal cells using Griess reagent. The LPS-activated production of prostaglandin E2 (PGE2) and cytokines (VEGF, IL-1β, IL-6 and TNF-α) was determined in both rat peritoneal cells and human peripheral blood mononuclear cells using ELISA.

Results

All sesquiterpenes (artemisinin, dihydroartemisinin, artemisinic acid, arteannuin B) significantly reduced production of PGE2. Arteannuin B also inhibited production of NO and secretion of cytokines. All NO, PGE2 and cytokines were suppressed by flavonoids casticin and chrysosplenol D. The coumarin derivative, 4-methylesculetin, was ineffective to change the production of any of these factors.

Conclusions

The inhibition of immune mediators of angiogenesis by sesquiterpene lactones and flavonoids may be one of the mechanisms of anticancer activity of Artemisia annua L.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

IL-:

interleukin-

LPS:

lipopolysaccharide

NO:

nitric oxide

PBMC:

peripheral blood mononuclear cells

PGE2:

prostaglandin E2

TNF:

tumor necrosis factor

VEGF:

vascular endothelial growth factor

References

  1. Al-Waili NS: A potential concept in the management of tumors with modulation of prostaglandin, nitric oxide and antioxidants. ScientificWorldJournal, 2007, 7, 466–478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Aldieri E, Atragene D, Bergandi L, Riganti C, Costamagna C, Bosia A, Ghigo D: Artemisinin inhibits inducible nitric oxide synthase and nuclear factor NF-κB activation. FEBS Lett, 2003, 552, 141–144.

    Article  CAS  PubMed  Google Scholar 

  3. Aung W, Sogawa C, Furukawa T, Saga T: Anticancer effect of dihydroartemisinin (DHA) in a pancreatic tumor model evaluated by conventional methods and optical imaging. Anticancer Res, 2011, 31, 1549–1558.

    CAS  PubMed  Google Scholar 

  4. Awale S, Linn TZ, Li F, Tezuka Y, Myint A, Tomida A, Yamori T et al.: Identification of chrysoplenetin from Vitex negundo as a potential cytotoxic agent against PANC-1 and a panel of 39 human cancer cell lines (JFCR-39). Phytother Res, 2011, 25, 1770–1775.

    Article  CAS  PubMed  Google Scholar 

  5. Benelli R, Lorusso G, Albini A, Noonan DM: Cytokines and chemokines as regulators of angiogenesis in health and disease. Curr Pharm Des, 2006, 12, 3101–3115.

    Article  CAS  PubMed  Google Scholar 

  6. Berger TG, Dieckmann D, Efferth T, Schultz ES, Funk JO, Baur A, Schuler G: Artesunate in the treatment of metastatic uveal melanoma-first experiences. Oncol Rep, 2005, 14, 1599–1603.

    CAS  PubMed  Google Scholar 

  7. Bertea CM, Freije JR, van der Woude H, Verstappen FW, Perk L, Marquez V, De Kraker JW et al.: Identification of intermediates and enzymes involved in the early steps of artemisinin biosynthesis in Artemisia annua. Planta Med, 2005, 71, 40–47.

    Article  CAS  PubMed  Google Scholar 

  8. Bradbury D, Clarke D, Seedhouse C, Corbett L, Stocks J, Knox A: Vascular endothelial growth factor induction by prostaglandin E2 in human airway smooth muscle cells is mediated by E prostanoid EP2/EP4 receptors and SP-1 transcription factor binding sites. J Biol Chem, 2005, 280, 29993–30000.

    Article  CAS  PubMed  Google Scholar 

  9. Brown GD: The biosynthesis of artemisinin (Qinghaosu) and the phytochemistry of Artemisia annua L. (Qinghao). Molecules, 2010, 15, 7603–7698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Carmeliet P, Jain RK: Angiogenesis in cancer and other diseases. Nature, 2000, 407, 249–257.

    Article  CAS  PubMed  Google Scholar 

  11. Cascone T, Gridelli C, Ciardiello F: Combined targeted therapies in non-small cell lung cancer: a winner strategy? Curr Opin Oncol, 2007, 19, 98–102.

    Article  PubMed  Google Scholar 

  12. Ding YB, Shi RH, Tong JD, Li XY, Zhang GX, Xiao WM, Yang JG et al.: PGE2 up-regulates vascular endothelial growth factor expression in MKN28 gastric cancer cells via epidermal growth factor receptor signaling system. Exp Oncol, 2005, 27, 108–113.

    CAS  PubMed  Google Scholar 

  13. Ferreira JF, Luthria DL, Sasaki T, Heyerick A: Flavonoids from Artemisia annua L. as antioxidants and their potential synergism with artemisinin against malaria and cancer. Molecules, 2010, 15, 3135–3170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Freitas S, Costa S, Azevedo C, Carvalho G, Freire S, Barbosa P, Velozo E et al.: Flavonoids inhibit angiogenic cytokine production by human glioma cells. Phytother Res, 2011, 25, 916–921.

    Article  CAS  PubMed  Google Scholar 

  15. Grandinetti CA, Goldspiel BR: Sorefanib and sunitinib: novel targered therapies for renal cell cancer. Pharmacotherapy, 2011, 27, 1125–1144.

    Article  Google Scholar 

  16. Haidara K, Zamir L, Shi QW, Batist G: The flavonoid casticin has multiple mechanisms of tumor cytotoxicity action. Cancer Lett, 2006, 242, 180–190.

    Article  CAS  PubMed  Google Scholar 

  17. He Q, Shi J, Shen XL, An J, Sun H, Wang L, Hu YJ et al.: Dihydroartemisinin upregulates death receptor 5 expression and cooperates with TRAIL to induce apoptosis in human prostate cancer cells. Cancer Biol Ther, 2010, 9, 819–824.

    Article  CAS  PubMed  Google Scholar 

  18. Higa S, Hirano T, Kotani M, Matsumoto M, Fujita A, Suemura M, Kawase I, Tanaka T: Fisetin, a flavonol, inhibits TH2-type cytokine production by activated human basophils. J Allergy Clin Immunol, 2003, 111, 1299–1306.

    Article  CAS  PubMed  Google Scholar 

  19. Hirano T, Higa S, Arimitsu J, Naka T, Shima Y, Ohshima S, Fujimoto M et al.: Flavonoids such as luteolin, fisetin and apigenin are inhibitors of interleukin-4 and interleukin-13 production by activated human basophils. Int Arch Allergy Immunol, 2004, 134, 135–140.

    Article  CAS  PubMed  Google Scholar 

  20. Chen HH, Zhou HJ, Wu GD, Lou XE: Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1. Pharmacology, 2004, 71, 1–9.

    Article  CAS  PubMed  Google Scholar 

  21. Chen T, Hwang H, Rose ME, Nines RG, Stoner GD: Chemopreventive properties of black raspberries in N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis: down-regulation of cyclooxygenase-2, inducible nitric oxide synthase, and c-Jun. Cancer Res, 2006, 66, 2853–2859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Iqbal S, Lenz HJ: Integration of novel agents in the treatment of colorectal cancer. Cancer Chemother Pharmacol, 2004, 54, Suppl 1, S32–S39.

    CAS  PubMed  Google Scholar 

  23. Jackson SA, Sahni S, Lee L, Luo Y, Nieduzak TR, Liang G, Chiang Y et al.: Design, synthesis and characterization of a novel class of coumarin-based inhibitors of inducible nitric oxide synthase. Bioorg Med Chem, 2005, 13, 2723–2739.

    Article  CAS  PubMed  Google Scholar 

  24. Kim HK, Cheon BS, Kim YH, Kim SY, Kim HP: Effects of naturally occurring flavonoids on nitric oxide production in the macrophage cell line RAW264.7 and their structure-activity relationships. Biochem Pharmacol, 1999, 58, 759–765.

    Article  CAS  PubMed  Google Scholar 

  25. Konkimalla VB, Blunder M, Korn B, Soomro SA, Jansen H, Chang W, Posner GH et al.: Effect of artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW264.7 mouse macrophage cells. Nitric Oxide, 2008, 19, 184–191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Krishna S, Bustamante L, Haynes RK, Staines HM: Artemisinins: their growing importance in medicine. Trends Pharmacol Sci, 2008, 29, 520–527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Leung KN, Leung PY, Kong LP, Leung PK: Immunomodulatory effects of esculetin (6,7-dihydroxycoumarin) on murine lymphocytes and peritoneal macrophages. Cell Mol Immunol, 2005, 2, 181–188.

    CAS  PubMed  Google Scholar 

  28. Lewis CE, Leek R, Harris A, McGee JO: Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages. J Leukoc Biol, 1995, 57, 747–751.

    Article  CAS  PubMed  Google Scholar 

  29. Li B, Zhang R, Li J, Zhang L, Ding G, Luo P, He S et al.: Antimalarial artesunate protects sepsis model mice against heat-killed Escherichia coli challenge by decreasing TLR4, TLR9 mRNA expressions and transcription factor NF-κB activation. Int Immunopharmacol, 2008, 8, 379–389.

    Article  CAS  PubMed  Google Scholar 

  30. Li WX, Cui CB, Cai B, Wang HY, Yao XS: Flavonoids from Vitex trifolia L. inhibit cell cycle progression at G2/M phase and induce apoptosis in mammalian cancer cells. J Asian Nat Prod Res, 2005, 7, 615–626.

    Article  CAS  PubMed  Google Scholar 

  31. Marletta MA, Yoon PS, Iyengar R, Leaf CD, Wishnok JS: Macrophage oxidation of L-arginine to nitrite and nitrate. Biochemistry, 1988, 27, 8706–8711.

    Article  CAS  PubMed  Google Scholar 

  32. Matsuda H, Morikawa T, Ohgushi T, Ishiwada T, Nishida N, Yoshikawa M: Inhibitors of nitric oxide production from the flowers of Angelica furcijuga: structures of hyuganosides IV and V. Chem Pharm Bull (Tokyo), 2005, 53, 387–392.

    Article  CAS  Google Scholar 

  33. Ogino H, Yano S, Kakiuchi S, Yamada T, Ikuta K, Nakataki E, Goto H et al.: Novel dual targeting strategy with vandetanib induces tumor cell apoptosis and inhibits angiogenesis in malignant pleural mesothelioma cells expressing RET oncogenic rearrangement. Cancer Lett, 2008, 265, 55–66.

    Article  CAS  PubMed  Google Scholar 

  34. Oklu R, Walker TG, Wicky S, Hesketh R: Angiogenesis and current antiangiogenic strategies for the treatment of cancer. J Vasc Interv Radiol, 2010, 21, 1791–1805.

    Article  PubMed  Google Scholar 

  35. Olszanecki R, Gebska A, Kozlovski VI, Gryglewski RJ: Flavonoids and nitric oxide synthase. J Physiol Pharmacol, 2002, 53, 571–584.

    CAS  PubMed  Google Scholar 

  36. Ono M, Yanaka T, Yamamoto M, Ito Y, Nohara T: New diterpenes and norditerpenes from the fruits of Vitex rotundifolia. J Nat Prod, 2002, 65, 537–541.

    Article  CAS  PubMed  Google Scholar 

  37. Raghav SK, Gupta B, Shrivastava A, Das HR: Inhibition of lipopolysaccharide-inducible nitric oxide synthase and IL-1_ through suppression of NF-κB activation by 3-(1’-1’-dimethyl-allyl)-6-hydroxy-7-methoxy-coumarin isolated from Ruta graveolens L. Eur J Pharmacol, 2007, 560, 69–80.

    Article  CAS  PubMed  Google Scholar 

  38. Sakurai T, Kudo M: Signaling pathways governing tumor angiogenesis. Oncology, 2011, 81, Suppl 1, 24–29.

    Article  CAS  Google Scholar 

  39. Singh NP, Panwar VK: Case report of a pituitary macroadenoma treated with artemether. Integr Cancer Ther, 2006, 5, 391–394.

    Article  PubMed  Google Scholar 

  40. Song X, Chen Y, Sun Y, Lin B, Qin Y, Hui H, Li Z et al.: Oroxylin A, a classical natural product, shows a novel inhibitory effect on angiogenesis induced by lipopolysaccharide. Pharmacol Rep, 2012, 64, 1189–1199.

    Article  CAS  PubMed  Google Scholar 

  41. Toomey DP, Murphy JF, Conlon KC: COX-2, VEGF and tumour angiogenesis. Surgeon, 2009, 7, 174–180.

    Article  CAS  PubMed  Google Scholar 

  42. Uneda S, Hata H, Matsuno F, Nagasaki A, Harada N, Mitsuya Y, Matsuzaki H, Mitsuya H: A nitric oxide synthase inhibitor, NG-nitro-l-arginine-methyl-ester, exerts potent antiangiogenic effects on plasmacytoma in a newly established multiple myeloma severe combined immunodeficient mouse model. Br J Haematol, 2003, 120, 396–404.

    Article  CAS  PubMed  Google Scholar 

  43. Wallaart TE, Pras N, Beekman AC, Quax WJ: Seasonal variation of artemisinin and its biosynthetic precursors in plants of Artemisia annua of different geographical origin: proof for the existence of chemotypes. Planta Med, 2000, 66, 57–62.

    Article  CAS  PubMed  Google Scholar 

  44. Wang GY, Ji B, Wang X, Gu JH: Anti-cancer effect of iNOS inhibitor and its correlation with angiogenesis in gastric cancer. World J Gastroenterol, 2005, 11, 3830–3833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang J, Zhou H, Zheng J, Cheng J, Liu W, Ding G, Wang L et al.: The antimalarial artemisinin synergizes with antibiotics to protect against lethal live Escherichia coli challenge by decreasing proinflammatory cytokine release. Antimicrob Agents Chemother, 2006, 50, 2420–2427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang JX, Hou LF, Yang Y, Tang W, Li Y, Zuo JP: SM905, an artemisinin derivative, inhibited NO and pro-inflammatory cytokine production by suppressing MAPK and NF-κB pathways in RAW264.7 macrophages. Acta Pharmacol Sin, 2009, 30, 1428–1435.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Watanabe K, Kawamori T, Nakatsugi S, Wakabayashi K: COX-2 and iNOS, good targets for chemoprevention of colon cancer. Biofactors, 2000, 12, 129–133.

    Article  CAS  PubMed  Google Scholar 

  48. Witaicenis A, Seito LN, Di Stasi LC: Intestinal antiinflammatory activity of esculetin and 4-methylesculetin in the trinitrobenzenesulphonic acid model of rat colitis. Chem Biol Interact, 2010, 186, 211–218.

    Article  CAS  PubMed  Google Scholar 

  49. Wu XH, Zhou HJ, Lee J: Dihydroartemisinin inhibits angiogenesis induced by multiple myeloma RPMI8226 cells under hypoxic conditions via downregulation of vascular endothelial growth factor expression and suppression of vascular endothelial growth factor secretion. Anticancer Drugs, 2006, 17, 839–848.

    Article  CAS  PubMed  Google Scholar 

  50. Xu W, Liu LZ, Loizidou M, Ahmed M, Charles IG: The role of nitric oxide in cancer. Cell Res, 2002, 12, 311–320.

    Article  PubMed  Google Scholar 

  51. Yance DRJ, Sagar SM: Targeting angiogenesis with integrative cancer therapies. Integr Cancer Ther, 2006, 5, 9–29.

    Article  CAS  PubMed  Google Scholar 

  52. Zeng Q-P, Zhang P-Z: Artesunate mitigates proliferation of tumor cells by alkylating heme-harboring nitric oxide synthase. Nitric Oxide, 2011, 24, 110–112.

    Article  CAS  PubMed  Google Scholar 

  53. Zhai DD, Zhong JJ: Simultaneous analysis of three bioactive compounds in Artemisia annua hairy root cultures by reversed-phase high-performance liquid chromatography-diode array detector. Phytochem Anal, 2010, 21, 524–530.

    Article  CAS  PubMed  Google Scholar 

  54. Zhang D, Yang L, Yang L-X, Wang M-Y, Tu Y-Y: Determination of artemisinin, arteannuin B and artemisinic acid in Herba Artemisiae Annuae by HPLC-UV-ELSD. Acta Pharmaceut Sinica, 2007, 42, 978–981.

    CAS  Google Scholar 

  55. Zhou HJ, Wang WQ, Wu GD, Lee J, Li A: Artesunate inhibits angiogenesis and downregulates vascular endothelial growth factor expression in chronic myeloid leukemia K562 cells. Vascul Pharmacol, 2007, 47, 131–138.

    Article  CAS  PubMed  Google Scholar 

  56. Zhu Z, Witte L: Inhibition of tumor growth and metastasis by targeting tumor-associated angiogenesis with antagonists to the receptors of vascular endothelial growth factor. Invest New Drugs, 1999, 17, 195–212.

    Article  CAS  PubMed  Google Scholar 

  57. Ziche M, Morbidelli L: Molecular regulation of tumour angiogenesis by nitric oxide. Eur Cytokine Netw, 2009, 20, 164–170.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Nanxiaojie 16, Dongzhimen Nei Avenue, Beijing, 100700, China

    Xiaoxin X. Zhu, Lan Yang, Yujie J. Li, Dong Zhang & Ying Chen

  2. Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20, Prague, Czech Republic

    Petra Kostecká & Zdeněk Zídek

  3. Institute of Pharmacology and Toxicology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic

    Eva Kmoníčková

Authors
  1. Xiaoxin X. Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yujie J. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Petra Kostecká
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eva Kmoníčková
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zdeněk Zídek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zdeněk Zídek.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhu, X.X., Yang, L., Li, Y.J. et al. Effects of sesquiterpene, flavonoid and coumarin types of compounds from Artemisia annua L. on production of mediators of angiogenesis. Pharmacol. Rep 65, 410–420 (2013). https://doi.org/10.1016/S1734-1140(13)71016-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/S1734-1140(13)71016-8

Key words

Search

Navigation