title: Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from St. John's wort that acts by induction of apoptosis.
abstract: Hyperforin is a plant derived antibiotic from St. John's wort. Here we describe a novel activity of hyperforin, namely its ability to inhibit the growth of tumour cells by induction of apoptosis. Hyperforin inhibited the growth of various human and rat tumour cell lines in vivo, with IC(50) values between 3-15 microM. Treatment of tumour cells with hyperforin resulted in a dose-dependent generation of apoptotic oligonucleosomes, typical DNA-laddering and apoptosis-specific morphological changes. In MT-450 mammary carcinoma cells hyperforin increased the activity of caspase-9 and caspase-3, and hyperforin-mediated apoptosis was blocked by the broad-range caspase inhibitor zVAD.fmk. When added to MT-450 cells, hyperforin, but not paclitaxel, induced a rapid loss of the mitochondrial transmembrane potential Deltapsi(m), and subsequent morphological changes such as homogenization and vacuolization of mitochondria. Monitoring of Deltapsi(m) revealed that the hyperforin-mediated mitochondrial permeability transition can not be prevented by zVAD.fmk. This indicates that mitochondrial permeabilization is a cause rather than a consequence of caspase activation. Moreover, hyperforin was capable of releasing cytochrome c from isolated mitochondria. These findings suggest that hyperforin activates a mitochondria-mediated apoptosis pathway. In vivo, hyperforin inhibited the growth of autologous MT-450 breast carcinoma in immunocompetent Wistar rats to a similar extent as the cytotoxic drug paclitaxel, without any signs of acute toxicity. Owing to the combination of significant antitumour activity, low toxicity in vivo and natural abundance of the compound, hyperforin holds the promise of being an interesting novel antineoplastic agent that deserves further laboratory and in vivo exploration.
authors.affiliation: Department of Dermatology, University of Freiburg, Hauptstrasse 7, D-79104 Freiburg, Germany. schempp@haut.ukl.uni-freiburg.de
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Schempp
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kirkin
authors.forename: Birgit
authors.initials: B
authors.lastname: Simon-Haarhaus
authors.forename: Astrid
authors.initials: A
authors.lastname: Kersten
authors.forename: Judit
authors.initials: J
authors.lastname: Kiss
authors.forename: Christian C
authors.initials: CC
authors.lastname: Termeer
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gilb
authors.forename: Thomas
authors.initials: T
authors.lastname: Kaufmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Borner
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Sleeman
authors.forename: Jan C
authors.initials: JC
authors.lastname: Simon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D020902:Hypericum / Q000737:chemistry*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D010696:Phloroglucinol / Q000031:analogs & derivatives; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; D003574:Cytochrome c Group; D013729:Terpenes; D010696:Phloroglucinol; D020169:Caspases; D019311:Staurosporine; C001654:hyperforin