Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Molecular Targets for Therapy (MTT)

Hyperforin inhibits MMP-9 secretion by B-CLL cells and microtubule formation by endothelial cells


We previously reported that hyperforin (HF), a natural phloroglucinol purified from Saint John's wort, can induce the apoptosis of leukemic cells from patients with B-cell lymphocytic leukemia (B-CLL) ex vivo. We show here that treatment of cultured B-CLL patients' cells with HF results in a marked inhibition of their capacity to secrete matrix metalloproteinase-9, an essential component in neo-angiogenesis through degradation of the extracellular matrix process. The phloroglucinol acts by decreasing the production of the latent 92 kDa pro-enzyme. The inhibitory effect of HF is associated with a decrease in VEGF release by the leukemic cells. Moreover, HF is found to prevent the formation of microtubules by human bone marrow endothelial cells cultured on Matrigel, evidencing its capacity to inhibit vessel formation. Our results show the antiangiogenesis activity of HF and strengthen its potential interest in the therapy of B-CLL.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others


  1. Ribatti D, Scavelli C, Roccaro AM, Crivellato E, Nico B, Vacca A . Hematopoietic cancer and angiogenesis. Stem Cells Dev 2004; 13: 484–495.

    Article  PubMed  Google Scholar 

  2. Kini AR, Kay NE, Peterson LC . Increased bone marrow angiogenesis in B cell chronic lymphocytic leukemia. Leukemia 2000; 14: 1414–1418.

    Article  CAS  PubMed  Google Scholar 

  3. Wolowiec D, Wozniak Z, Potoczek S, Ganczarski G, Wrobel T, Kuliczkowski K et al. Bone marrow angiogenesis and proliferation in B-cell chronic lymphocytic leukemia. Anal Quant Cytol Histol 2004; 26: 263–270.

    PubMed  Google Scholar 

  4. Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenaker G . Biochemistry and molecular biology of gelatinase B or matrix metalloprotease-9 (MMP-9). Critl Rev Biochem Mol Biol 2002; 37: 375–536.

    Article  CAS  Google Scholar 

  5. Bauvois B, Dumont J, Mathiot C, Kolb JP . Production of matrix metalloproteinase-9 in early stage B-CLL: suppression by interferons. Leukemia 2002; 16: 791–798.

    Article  CAS  PubMed  Google Scholar 

  6. Molica S, Vitelli G, Levato D, Giannarelli D, Vacca A, Cuneo A et al. Increased serum levels of matrix metalloproteinase-9 predict clinical outcome of patients with early B-cell chronic lymphocytic leukaemia. Eur J Haematol 2003; 70: 373–378.

    Article  CAS  PubMed  Google Scholar 

  7. Kamiguti AS, Lee ES, Till KJ, Harris RJ, Glenn MA, Lin K et al. The role of matrix metalloproteinase 9 in the pathogenesis of chronic lymphocytic leukaemia. Br J Haematol 2004; 125: 128–140.

    Article  CAS  PubMed  Google Scholar 

  8. Barnes J, Anderson LA, Phillipson JD . St John's wort (Hypericum perforatum L.): a review of its chemistry, pharmacology and clinical properties. J Pharm Pharmacol 2001; 53: 583–600.

    Article  CAS  PubMed  Google Scholar 

  9. Singer A, Wonnemann M, Muller WE . Hyperforin, a major antidepressant constituent of St John's Wort, inhibits serotonin uptake by elevating free intracellular Na+. J Pharmacol Exp Ther 1999; 290: 1363–1368.

    CAS  PubMed  Google Scholar 

  10. Treiber K, Singer A, Henke B, Muller WE . Hyperforin activates nonselective cation channels (NSCCs). Br J Pharmacol 2005; 145: 75–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schempp CM, Pelz K, Wittmer A, Schopf E, Simon JC . Antibacterial activity of hyperforin from St John's wort, against multiresistant Staphylococcus aureus and gram-positive bacteria. Lancet 1999; 353: 2129.

    Article  CAS  PubMed  Google Scholar 

  12. Heilmann J, Winkelmann K, Sticher O . Studies on the antioxidative activity of phloroglucinol derivatives isolated from hypericum species. Planta Med 2003; 69: 202–206.

    Article  CAS  PubMed  Google Scholar 

  13. Albert D, Zundorf I, Dingermann T, Muller WE, Steinhilber D, Werz O . Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase. Biochem Pharmacol 2002; 64: 1767–1775.

    Article  CAS  PubMed  Google Scholar 

  14. Zou L, Harkey MR, Henderson GL . Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity. Life Sci 2002; 71: 1579–1589.

    Article  CAS  PubMed  Google Scholar 

  15. Schempp CM, Winghofer B, Ludtke R, Simon-Haarhaus B, Schopf E, Simon JC . Topical application of St John's wort (Hypericum perforatum L.) and of its metabolite hyperforin inhibits the allostimulatory capacity of epidermal cells. Br J Dermatol 2000; 142: 979–984.

    Article  CAS  PubMed  Google Scholar 

  16. Hostanska K, Reichling J, Bommer S, Weber M, Saller R . Hyperforin a constituent of St John's wort (Hypericum perforatum L.) extract induces apoptosis by triggering activation of caspases and with hypericin synergistically exerts cytotoxicity towards human malignant cell lines. Eur J Pharm Biopharm 2003; 56: 121–132.

    Article  CAS  PubMed  Google Scholar 

  17. Schempp CM, Kirkin V, Simon-Haarhaus B, Kersten A, Kiss J, Termeer CC et al. Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from St John's wort that acts by induction of apoptosis. Oncogene 2002; 21: 1242–1250.

    Article  CAS  PubMed  Google Scholar 

  18. Quiney C, Billard C, Faussat AM, Salanoubat C, Ensaf A, Naït-Si Y et al. Pro-apoptotic properties of hyperforin in leukemic cells from patients with B-cell chronic lymphocytic leukemia. Leukemia 2006, (in press).

  19. Zhao H, Dugas N, Mathiot C, Dugas B, Sigaux F, Kolb JP . B-cell chronic lymphocytic leukemia cells express a functional inducible nitric oxide synthase displaying anti-apoptotic activity. Blood 1998; 92: 1031–1043.

    CAS  PubMed  Google Scholar 

  20. Lehr JE, Pienta KJ . Preferential adhesion of prostate cancer cells to a human bone marrow endothelial cell line. J Natl Cancer Inst 1998; 90: 118–123.

    Article  CAS  PubMed  Google Scholar 

  21. Fourneron JD, Naït-Si Y . Effect of eluent pH on HPLC/UV analysis of hyperforin. Phytochem Analysis 2006, (in press).

  22. Billard C, Kern C, Tang R, Ajchenbaum-Cymbalista F, Kolb JP . Flavopiridol down-regulates the expression of both the inducible NO synthase and p27kip1 in malignant cells from B-cell chronic lymphocytic leukemia. Leukemia 2003; 17: 2438–2443.

    Article  Google Scholar 

  23. Kern C, Cornuel J, Billard C, Tang R, Rouillard D, Steunou V et al. Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway. Blood 2004; 103: 679–688.

    Article  CAS  PubMed  Google Scholar 

  24. Chen W, Valamanesh F, Mirshahi T, Soria J, Tang R, Agarwal MK et al. Aldosterone signaling modifies capillary formation by human bone marrow endothelial cells. Vasc Pharmacol 2004; 40: 269–277.

    Article  CAS  Google Scholar 

  25. Aguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D et al. Angiogenesis in acute and chronic leukemias and myelodysplatic syndromes. Blood 2000; 96: 2240–2245.

    CAS  PubMed  Google Scholar 

  26. Chen H, Treweeke AT, West DC, Till KJ, Cawley JC, Zuzel M et al. In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells. Blood 2000; 96: 3181–3187.

    CAS  PubMed  Google Scholar 

  27. Uggla C, Aguilar-Santelises M, Rosen A, Mellstedt H, Jondal M . Spontaneous production of interleukin 1 activity by chronic lymphocytic leukemic cells. Blood 1987; 70: 1851–1857.

    CAS  PubMed  Google Scholar 

  28. Belotti D, Paganoni P, Manenti L, Garofalo A, Marchini S, Taraboletti G et al. Matrix metalloproteinases (MMP9 and MMP2) induce the release of vascular endothelial growth factor (VEGF) by ovarian carcinoma cells: implications for ascites formation. Cancer Res 2003; 63: 5224–5229.

    CAS  PubMed  Google Scholar 

  29. Hiratsuka S, Nakamura K, Iwai S, Murakami M, Itoh T, Kijima H et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2002; 2: 289–300.

    Article  CAS  PubMed  Google Scholar 

  30. Kay NE, Bone ND, Tschumper RC, Howell KH, Geyer SM, Dewald GW et al. B-CLL cells are capable of synthesis and secretion of both pro- and anti-angiogenic molecules. Leukemia 2002; 16: 911–919.

    Article  CAS  PubMed  Google Scholar 

  31. Bairey O, Boycov O, Kaganovsky E, Zimra Y, Shaklai M, Rabizadeh E . All three receptors for vascular endothelial growth factor (VEGF) are expressed on B-chronic lymphocytic leukemia (CLL) cells. Leuk Res 2004; 28: 243–248.

    Article  CAS  PubMed  Google Scholar 

  32. Dias S, Hattori K, Zhu Z, Heissig B, Choy M, Lane W et al. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J Clin Invest 2000; 106: 511–521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hayashibara T, Yamada Y, Onimaru Y, Tsutsumi C, Nakayama S, Mori N et al. Matrix metalloproteinase-9 and vascular endothelial growth factor: a possible link in adult T-cell leukaemia cell invasion. Br J Haematol 2002; 116: 94–102.

    Article  CAS  PubMed  Google Scholar 

  34. Ringshausen I, Dechow T, Schneller F, Weick K, Oelsner M, Peschel C et al. Constitutive activation of the MAPkinase p38 is critical for MMP-9 production and survival of B-CLL cells on bone marrow stromal cells. Leukemia 2004; 18: 1964–1970.

    Article  CAS  PubMed  Google Scholar 

  35. Nguyen M, Arkell J, Jackson CJ . Human endothelial gelatinases and angiogenesis. Int J Biochem Cell Biol 2001; 33: 960–970.

    Article  CAS  PubMed  Google Scholar 

  36. Dona M, Dell'Aica I, Pezzato E, Sartor L, Calabrese F, Della Barbera M et al. Hyperforin inhibits cancer invasion and metastasis. Cancer Res 2004; 64: 6225–6232.

    Article  CAS  PubMed  Google Scholar 

Download references


This work was supported by INSERM, Canceropôle Ile-de-France and by a grant from ARC (#3322). CQ was supported by a grant of the Société Française d'Hématologie. We thank the clinicians of the Department of Hematology of the Hôtel-Dieu hospital, and Mrs S Pasco-Dubrulle for technical assistance.

Author information

Authors and Affiliations


Corresponding author

Correspondence to J-P Kolb.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Quiney, C., Billard, C., Mirshahi, P. et al. Hyperforin inhibits MMP-9 secretion by B-CLL cells and microtubule formation by endothelial cells. Leukemia 20, 583–589 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


This article is cited by


Quick links