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 mM. Treatment of tumour cells with hyperforin resulted in a dose-dependent generation of apoptotic oligonucleosomes, typical DNA-laddering and apoptosis-speci®c 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 Dc m , and subsequent morphological changes such as homogenization and vacuolization of mitochondria. Monitoring of Dc 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 ®ndings 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 signi®cant 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.

Pro-apoptotic properties of hyperforin in leukemic cells from patients with B-cell chronic lymphocytic leukemia

“…Indeed, HF elicited PS externalization, Our results showing that DNA fragmentation and several effects of HF described here, including PARP cleavage, are inhibited by the general caspase inhibitor z-VAD-fmk and that caspase-3 activity is stimulated highlight the role of the caspase pathway in HF-mediated apoptosis of B-CLL cells. These results are in agreement with previous reports on other types of tumor cells, 13,14 except that only a slight caspase-8 activation was found here. HF is not known to bind to a receptor displaying a death domain and, with the exception of the D(1) dopamine receptor, it does not interact with biogenic amine receptors and transporters.…”

“…11 Recently, it was reported that extracts of St John's wort containing HF induce growth inhibition and apoptosis of human and rat malignant cells in vitro as well as in vivo. 12,13 Similar effects, associated with activation of caspases, were also shown with the myeloid leukemia cell lines K562 and U937. 14 However, it is not known whether HF could exert activity in B-cell chronic lymphocytic leukemia (B-CLL), a malignancy which results from a defect of apoptosis rather than an impaired control of lymphoproliferation.…”

Hyperforin Inhibits Cancer Invasion and Metastasis

“…Inhibition of proliferation has been reported also in vivo (6), and the cytotoxic effect of Hyp on human malignant cells was correlated with the induction of caspase-driven apoptosis (7). This finding could be of great oncological relevance, but no study has yet validated Hyp as an anticancer lead by demonstration of its effectiveness against invasive and metastatic aggressiveness.…”

“…However, an even more pronounced protective effect should be registered in spontaneous metastasis models where more steps of the process can be hindered by Hyp, including cell proliferation and survival, as already proved (ref. 6 and here), as well as intravasation.…”

“…Spurred by the results of controlled but limited trials showing that mild to moderate depression can benefit from oral administration of extracts from this plant, the NIH launched in March 2003 a large-scale clinical trial to determine how the herbal agent fits into the overall management of the disorder and confirm its efficacy. 6 St. John's extracts are a rich source of unique natural products, and the prenylated acylphloroglucinol hyperforin (Hyp) has emerged as key player for the antidepressant activity of the plant (1), as well as for its severe interactions with several prescription drugs (2). Although the antidepressant target of Hyp has thus far remained elusive, this compound turned out to be the most powerful ligand ever discovered for the pregnane-X-receptor (3), a nuclear transcription factor underlying the activation of the P450 cytochrome system, and serving as a xenobiotic sensor to preserve chemical homeostasis.…”