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 IC50 values between 3–15 μM. 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 Δψm, and subsequent morphological changes such as homogenization and vacuolization of mitochondria. Monitoring of Δψm 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.
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Acknowledgements
We thank Norma Howells and Jonathan Ward for animal care; Marco Averbeck and Bernhard Kremer for technical assistance with the video microscope; and Stefan Martin for critically reading the manuscript. CM Schempp was supported by the Carl und Veronika Carstens-Stiftung and the Paul und Yvonne Gillet-Stiftung (S012/01.221/97). T Kaufmann and C Borner were supported by the Swiss National Science Foundation (31-57236.99). Judit Kiss is a scientific exchange fellow of the Semmelweis University, Budapest, Hungary, supported by a grant from the University Medical Center Freiburg.
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Schempp, C., Kirkin, V., Simon-Haarhaus, B. et al. Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from St. John's wort that acts by induction of apoptosis. Oncogene 21, 1242–1250 (2002). https://doi.org/10.1038/sj.onc.1205190
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DOI: https://doi.org/10.1038/sj.onc.1205190
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