Hyperforin and aristoforin inhibit lymphatic endothelial cell proliferation in vitro and suppress tumor-induced lymphangiogenesis in vivo.

Abstract

The phloroglucinol derivative hyperforin, a major bioactive constituent of St. John's wort, is increasingly recognized as being able to regulate a variety of pathobiological processes and, thus, to possess potential therapeutic properties. In the context of cancer, hyperforin induces the apoptosis of cancer cells, inhibits angiogenesis and suppresses metastasis formation. Here, we report a new pharmacological function of hyperforin and its stabilized derivative aristoforin, namely the suppression of lymphatic endothelial cell (LEC) growth and lymphangiogenesis. At concentrations less than 10 microM, we found that these compounds induce cell cycle arrest of LECs, and at higher concentrations induce apoptosis. The loss of mitochondrial membrane potential and the activation of caspase-9 during the induction of apoptosis indicate that the intrinsic pathway of apoptosis is stimulated by these compounds, similar to the situation in tumor cells. In thoracic duct ring outgrowth assays, hyperforin and aristoforin both inhibited lymphangiogenesis, as evidenced by the suppression of lymphatic capillary outgrowth. In an in vivo animal model, both compounds were able to inhibit tumor-induced lymphangiogenesis. Together these data substantiate a new role for hyperforin and its derivatives as suppressors of lymphangiogenesis, and support their further investigation as potential anticancer drugs that target tumor growth and metastasis at multiple levels.

• Authors: Melanie Rothley, Anja Schmid, Wilko Thiele, Vivien Schacht, Diana Plaumann, Michael Gartner, Aybike Yektaoglu, Françoise Bruyère, Agnès Noël, Athanassios Giannis, Jonathan P Sleeman
• Journal: International journal of cancer (Int J Cancer) Vol. 125 Issue 1 Pg. 34-42 (Jul 01 2009) ISSN: 1097-0215 [Electronic] United States
• PMID: 19326439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aristoforin
• Bridged Bicyclo Compounds
• Proto-Oncogene Proteins c-bcl-2
• Terpenes
• Cytochromes c
• Phloroglucinol
• Caspase 3
• Caspase 8
• hyperforin

Topics

• Animals
• Aorta, Thoracic (drug effects)
• Apoptosis (drug effects)
• Bridged Bicyclo Compounds (pharmacology)
• Caspase 3 (metabolism)
• Caspase 8 (metabolism)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cytochromes c (metabolism)
• Endothelial Cells (drug effects)
• Endothelium, Vascular (cytology, drug effects, metabolism)
• Female
• Humans
• In Vitro Techniques
• Lymphangiogenesis (drug effects)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, metabolism)
• Neoplasms, Experimental (pathology)
• Phloroglucinol (analogs & derivatives, pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Rats
• Rats, Wistar
• Terpenes (pharmacology)
• Xenograft Model Antitumor Assays