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.