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Hyperforin Inhibits Cancer Invasion and Metastasis

Departments of ¹ Experimental Biomedical Sciences, ² Pathology, and ³ Biological Chemistry, Medical School of Padova; ⁴ DISCAFF, University of Piemonte Orientale, Novara; and ⁵ Department of Biology, University of Padova, Padova, Italy

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 µmol/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 µmol/L), followed by cathepsin G and urokinase-type plasminogen activator, whereas that of the matrix metalloproteinases (MMPs) 2 and 9 showed an IC₅₀ > 100 µmol/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 µmol/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.

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