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Hyperforin and aristoforin inhibit lymphatic endothelial cell proliferation in vitro and suppress tumor‐induced lymphangiogenesis in vivo
Author(s) -
Rothley Melanie,
Schmid Anja,
Thiele Wilko,
Schacht Vivien,
Plaumann Diana,
Gartner Michael,
Yektaoglu Aybike,
Bruyère Françoise,
Noël Agnès,
Giannis Athanassios,
Sleeman Jonathan P.
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24295
Subject(s) - lymphangiogenesis , hyperforin , angiogenesis , cancer research , apoptosis , microbiology and biotechnology , lymphatic system , chemistry , in vivo , lymphatic endothelium , biology , metastasis , pharmacology , immunology , cancer , biochemistry , genetics , hypericum perforatum
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 μM, 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. © 2009 UICC