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DOI: 10.1055/s-2005-871303
© Georg Thieme Verlag KG Stuttgart · New York
Hyperforin acts as an Angiogenesis Inhibitor in vitro and in vivo
Publikationsverlauf
Received: March 25, 2005
Accepted: May 18, 2005
Publikationsdatum:
19. September 2005 (online)
Abstract
Hyperforin is a plant compound from Hypericum perforatum that inhibits tumor cell proliferation in vitro by induction of apoptosis. Here, we report that hyperforin also acts as an angiogenesis inhibitor in vitro and in vivo. In vitro, hyperforin blocked microvessel formation of human dermal microvascular endothelial cells (HDMEC) on a complex extracellular matrix. Furthermore, hyperforin reduced proliferation of HDMEC in a dose-dependent manner, without displaying toxic effects or inducing apoptosis of the cells. To evaluate the antiangiogenic activity of hyperforin in vivo, Wistar rats were subcutaneously injected with MT-450 mammary carcinoma cells and were treated with peritumoral injections of hyperforin or solvent. Hyperforin significantly inhibited tumor growth, induced apoptosis of tumor cells and reduced tumor vascularization, as shown by in situ staining of CD31-positive microvessels in the tumor stroma. These data suggest that, in addition to the induction of tumor cell apoptosis, hyperforin can also suppress angiogenesis by a direct, non-toxic effect on endothelial cells.
Key words
Angiogenesis - apoptosis - endothelial cells - microvessels - CD31
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References
- 1 Linde K, Ramirez G, Mulrow C D, Pauls A, Weidenhammer W, Melchart D. St. John’s wort for depression - an overview and metaanalysis of randomized clinical trials. Br Med J. 1996; 313 253-8
- 2 Kaul R. Johanniskraut. Botanik, Inhaltsstoffe, Qualitätskontrolle, Pharmakologie, Toxikologie und Klinik. Stuttgart; Wiss Verlagsges; 2000.
- 3 Bystrov N S, Chernov B K, Dobrynin V N, Kolosov M N. The structure of hyperforin. Tetrahedron Lett. 1975; 16 2791-4
- 4 Maisenbacher P, Kovar K A. Analysis and stability of Hyperici oleum. Planta Med. 1992; 58 351-4
- 5 Gurevich A I, Dobrynin V N, Kolosov M N, Popravko S A, Ryabova I D, Chernov B K. et al . Hyperforin, an antibiotic from Hypericum perforatum L. Antibiotiki. 1971; 16 510-3
- 6 Schempp C M, Pelz K, Wittmer A, Schöpf E, Simon J C. Antibacterial activity of hyperforin from St John’s wort, against multiresistant Staphylococcus aureus and Gram-positive bacteria. Lancet. 1999; 353 2129
- 7 Müller W E, Singer A, Wonnemann M, Hafner U, Rolli M, Schäfer C. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of Hypericum extract. Pharmacopsychiatry. 1998; 31 (Suppl 1) 16-21
- 8 Albert D, Zundorf I, Dingermann T, Muller W E, Steinhilber D, Werz O. Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase. Biochem Pharmacol. 2002; 64 1767-75
- 9 Schempp C M, Winghofer B, Lüdtke R, Simon-Haarhaus B, Schöpf E, Simon J C. 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; 142 979-84
- 10 Schempp C M, Kirkin V, Simon-Haarhaus B, Kersten A, Kiss J, Termeer C C. 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 1242-50
- 11 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; 56 121-32
- 12 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 6225-32
- 13 Uhr J W, Scheuermann R H, Street N E, Vitetta E S. Cancer dormancy: opportunities for new therapeutic approaches. Nat Med. 1997; 3 505-9
- 14 Gastl G, Hermann T, Steurer M, Zmija J, Gunsilius E, Unger C, Kraft A. Angiogenesis as a target for tumor treatment. Oncology. 2001; 54 177-84
- 15 Liekens S, de Clercq E, Neyts J. Angiogenesis: regulators and clinical applications. Biochem Pharmacol. 2001; 61 253-70
- 16 Tanigawa N, Amaya H, Matsumura M, Lu C, Kitaoka A, Matsuyama K. et al . Tumor angiogenesis and mode of metastasis in patients with colorectal cancer. Cancer Res. 1997; 57 1043-6
- 17 Bicknell R, Harris A L. Mechanisms and therapeutic implications of angiogenesis. Curr Opin Oncol. 1996; 8 60-5
- 18 Carmeliet P, Jain R K. Angiogenesis in cancer and other diseases. Nature. 2000; 407 249-57
- 19 Detmar M. Tumor angiogenesis. J Invest Dermatol Symp Proc. 2000; 5 20-3
- 20 Pluda J M. Tumor-associated angiogenesis: mechanisms, clinical implications, and therapeutic strategies. Semin Oncol. 1997; 24 203-18
- 21 Twardowski P, Gradishar W J. Clinical trials of antiangiogenic agents. Curr Opin Oncol. 1997; 9 584-9
- 22 Weinstat-Saslow D, Steeg P S. Angiogenesis and colonization in the tumor metastatic process: basic and applied advances. FASEB J. 1994; 8 401-7
- 23 Drevs J, Hofmann I, Hugenschmidt H, Wittig C, Madjar H, Müller M. et al . Effects of PTK787/ZK 222 584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. Cancer Res. 2000; 60 4819-24
- 24 Sleeman J P, Kim U, LePendu J, Howells N, Coquerelle T, Ponta H. et al . Inhibition of MT-450 rat mammary tumour growth by antibodies recognising subtypes of blood group antigen B. Oncogene. 1999; 8 4485-94
- 25 Averbeck M, Braun T, Pfeifer G, Sleeman J P, Dudda J, Martin S F. et al . Early cytoskeletal rearrangement during dendritic cell maturation enhances synapse formation and Ca(2+) signaling in CD8(+) T cells. Eur J Immunol. 2004; 34 2708-19
- 26 Schempp C M, Simon-Haarhaus B, Termeer C C, Simon J C. Hypericin photo-induced apoptosis of Jurkat cells involves the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and activation of caspase-8. FEBS Lett. 2001; 493 26-30
- 27 Weidner N. Intratumoral microvessel density as a prognostic factor in cancer. Am J Pathol. 1995; 147 9-19
- 28 Siemeister G, Schirner M, Weindel K, Reusch P, Menrad A, Marme D. Two independent mechanisms essential for tumor angiogenesis: inhibition of human melanoma xenograft growth by interfering with either the vascular endothelial growth factor receptor pathway or the Tie-2 pathway. Cancer Res. 1999; 59 3185-91
- 29 Nör J E, Christensen J, Mooney D J, Polverini P J. Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Pathol. 1999; 154 375-84
- 30 del Valle-Perez B, Martinez-Estrada O M, Vilaro S, Ventura F, Vinals F. cAMP inhibits TGFbeta1-induced in vitro angiogenesis. FEBS Lett. 2004; 569 105-11
- 31 Ogawa H, Rafiee P, Fisher P J, Johnson N A, Otterson M F, Binion D G. Sodium butyrate inhibits angiogenesis of human intestinal microvascular endothelial cells through COX-2 inhibition. FEBS Lett. 2003; 554 88-94
- 32 Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M. et al . Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002; 8 128-35
Christoph M. Schempp
Department of Dermatology
University of Freiburg
Hauptstrasse 7
79104 Freiburg
Germany
Fax: +49-761-270-6829
eMail: cschempp@haut.ukl.uni-freiburg.de
- www.thieme-connect.de/ejournals/toc/plantamedica