Hyperforin inhibits cancer invasion and metastasis.

Abstract

Hyperforin (Hyp), the major lipophilic constituent of St. John's wort, was assayed as a stable dicyclohexylammonium salt (Hyp-DCHA) for cytotoxicity and inhibition of matrix proteinases, tumor invasion, and metastasis. Hyp-DCHA triggered apoptosis-associated cytotoxic effect in both murine (C-26, B16-LU8, and TRAMP-C1) and human (HT-1080 and SK-N-BE) tumor cells; its effect varied, with B16-LU8, HT-1080, and C-26 the most sensitive (IC50 = 5 to 8 micromol/L). At these concentrations, a marked and progressive decline of growth was observed in HT-1080 cells, whereas untransformed endothelial cells were only marginally affected. Hyp-DCHA inhibited in a dose-dependent and noncompetitive manner various proteinases instrumental to extracellular matrix degradation; the activity of leukocyte elastase was inhibited the most (IC50 = 3 micromol/L), followed by cathepsin G and urokinase-type plasminogen activator, whereas that of the matrix metalloproteinases (MMPs) 2 and 9 showed an IC50 > 100 micromol/L. Nevertheless, inhibition of extracellular signal-regulated kinase 1/2 constitutive activity and reduction of MMP-2 and MMP-9 secretion was triggered by 0.5 micromol/L Hyp-DCHA to various degrees in different cell lines, the most in C-26. Inhibition of C-26 and HT-1080 cell chemoinvasion (80 and 54%, respectively) through reconstituted basement membrane was observed at these doses. Finally, in mice that received i.v. injections of C-26 or B16-LU8 cells, daily i.p. administration of Hyp-DCHA-without reaching tumor-cytotoxic blood levels-remarkably reduced inflammatory infiltration, neovascularization, lung weight (-48%), and size of experimental metastases with C-26 (-38%) and number of lung metastases with B16-LU8 (-22%), with preservation of apparently healthy and active behavior. These observations qualify Hyp-DCHA as an interesting lead compound to prevent and contrast cancer spread and metastatic growth.

• Authors: Massimo Donà, Isabella Dell'Aica, Elga Pezzato, Luigi Sartor, Fiorella Calabrese, Mila Della Barbera, Arianna Donella-Deana, Giovanni Appendino, Anna Borsarini, Rosy Caniato, Spiridione Garbisa
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 17 Pg. 6225-32 (Sep 01 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15342408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bridged Bicyclo Compounds
• Cyclohexylamines
• Quaternary Ammonium Compounds
• Terpenes
• dicyclohexylamine
• Phloroglucinol
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• Serine Endopeptidases
• Gelatinases
• hyperforin

Topics

• Adenocarcinoma (blood, drug therapy, pathology)
• Animals
• Apoptosis (drug effects)
• Bridged Bicyclo Compounds
• Cell Division (drug effects)
• Cell Survival (drug effects)
• Colonic Neoplasms (blood, drug therapy, pathology)
• Cyclohexylamines (blood, pharmacology)
• Enzyme Activation (drug effects)
• Fibrosarcoma (blood, drug therapy, pathology)
• Gelatinases (biosynthesis)
• Humans
• Lung Neoplasms (blood, drug therapy, secondary)
• Male
• Melanoma, Experimental (blood, drug therapy, pathology)
• Mice
• Mice, Inbred BALB C
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases (metabolism)
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplasms (blood, drug therapy, pathology)
• Neuroblastoma (blood, drug therapy, pathology)
• Phloroglucinol (analogs & derivatives)
• Quaternary Ammonium Compounds (blood, pharmacology)
• Serine Endopeptidases (metabolism)
• Terpenes (blood, pharmacology)