Hyperforin inhibits cancer invasion and metastasis.
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.
Donà
Massimo
M
Department of Experimental Biomedical Sciences, Medical School of Padova, Italy.
Dell'Aica
Isabella
I
Pezzato
Elga
E
Sartor
Luigi
L
Calabrese
Fiorella
F
Della Barbera
Mila
M
Donella-Deana
Arianna
A
Appendino
Giovanni
G
Borsarini
Anna
A
Caniato
Rosy
R
Garbisa
Spiridione
S
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001643:Bridged Bicyclo Compounds; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D003514:Cyclohexylamines / Q000097:blood / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005354:Fibrosarcoma / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D018093:Gelatinases / Q000096:biosynthesis; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008546:Melanoma, Experimental / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D009447:Neuroblastoma / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D010696:Phloroglucinol / Q000031:analogs & derivatives; D000644:Quaternary Ammonium Compounds / Q000097:blood / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism; D013729:Terpenes / Q000097:blood / Q000494:pharmacology*
D001643:Bridged Bicyclo Compounds; D003514:Cyclohexylamines; D000644:Quaternary Ammonium Compounds; D013729:Terpenes; C011769:dicyclohexylamine; D010696:Phloroglucinol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D012697:Serine Endopeptidases; D018093:Gelatinases; C001654:hyperforin