Extracts of the plant St John's wort, Hyperforin perforatum L., have been used for centuries in traditional medicine, notably for the treatment of depression. One of their main lipophilic components, a natural prenylated phloroglucinol termed hyperforin (HF), has been identified as the major molecule responsible for the antidepressant effects of this plant. Within the last few years, a number of studies have demonstrated that HF displays, in addition, several other biological properties of potential pharmacological interest. They include an antibacterial capacity and inhibitory effects on inflammatory mediators. It is worth noting that HF also promotes apoptosis of various cancer cells from solid tumors and hematological malignancies, including B-cell chronic lymphocytic leukemia. In addition, HF inhibits the capacity of migration and invasion of different tumor cells, as well as exhibiting antiangiogenic effects. Altogether, these properties qualify HF as a lead structure for the development of new therapeutic molecules in the treatment of various diseases, including some malignant tumors.
In a search for the discovery of new therapeutic agents for B-cell chronic lymphocytic leukemia (B-CLL), our group became interested in testing the effects of hyperforin (HF). This interest was based on the biochemical properties of this herbal compound and its structural similarity with molecules known to exert proapoptotic effects on various cancer cells. We recently reported that HF promoted apoptosis of B-CLL cells1 inhibited the release of matrix metalloprotease 9, MMP-9, a protease likely involved in the early steps of neo-angiogenesis, and disrupted the spontaneous formation of tubules by human bone marrow endothelial cells2. HF also inhibited in B-CLL cells the activity of P-glycoprotein (P-gp), a member of the ABC (ATP-binding cassette) transporter involved in the resistance of leukemic cells to commonly used chemotherapeutic agents. Several groups have recently reported comparable findings in various cell types and HF has gained consideration as a putative lead compound for the therapy of different cancerous diseases. This review is therefore aimed at describing the properties of HF with special emphasis on its development as a new therapy for various cancers and leukemias.
Identification of HF as an active component of St John's wort
Extracts of the herbaceous plant St John's wort (SJW) (Hypericum perforatum L.) have been utilized in traditional medicine for the treatment of various illnesses, including infections, respiratory diseases and skin wounds, their main indication being for the therapy of depression.3 Nowadays, it is still recommended for patients suffering from mild depression, anxiety and neuralgia. Standardized extracts of SJW are effective in these pathologies and present less side effects than classical antidepressants.4 These extracts displayed antibacterial properties,5 leading to the hypothesis that they contained a new antibiotic named HF.6 The same group isolated this compound and established its chemical structure.7 This molecule consists of a phloroglucinol backbone with isoprene chains that confer its lipophilic properties (Figure 1).
HF is present in the flowers and leaves, notably in the oil glands, of the plant H. perforatum L. and other varieties of Hypericum belonging to the Hypericaceae family. HF is a natural prenylated phloroglucinol representing one of the main lipophilic compounds in SJW extracts. The biosynthesis of HF involves five isoprenoid moieties, which are predominantly derived via the deoxyxylulose phosphate pathway, whereas the phloroglucinol moiety is generated via a polyketide-type mechanism.8
H. perforatum L. contains a second phloroglucinol, adHF, with a methyl group at the extremity of the lateral branch containing a keto group and many other biologically active components. They include naphthodianthrones, such as hypericin, flavonoids, procyanidines, xanthones, essential oils, tannins, phenylpropanes and a complex mixture of hydrosoluble constituents (peptides, polysaccharides, organic acids, amino acids).9 The major constituents have been characterized using high-performance liquid chromatography-electrospray mass spectrometry (HPLC-ESI-MS).10 Many are endowed with biological activities and identifying which is responsible for the various therapeutic properties attributed to SJW extracts is a difficult task, complicated by the fact that some of these derivatives act in synergy. For instance, hypericin is a strong natural photosensitizer and has potential application for antitumoral photodynamic therapy11 and the flavonoid quercitin contributes to the anti-inflammatory properties of SJW.12 HF, however, has gained much attention as the main active component with antidepressant effects,13 and also as a molecule displaying pleiotropic activities of putative therapeutic interests.14
Alternative therapies are frequently used by patients suffering from depression and anxiety. SJW extracts have become widely used in these pathologies through their capacity to inhibit the reuptake of monoamines, serotonin, dopamine, noradrenaline and the amino-acid neurotransmitters γ-aminobutyric acid (GABA) and glutamate.15 SJW extracts exert this reuptake inhibition non-competitively by enhancing intracellular Na+ concentrations. At a receptor level, chronic treatment with hypericum downregulates ß1-adrenoceptor, whereas it upregulates postsynaptic 5-hydroxytryptamine (5-HT)1A receptors and 5-HT2 receptors.16
HF is the main component responsible for the antidepressant effects, yet other constituents may be involved.3, 17 Hypericin and pseudohypericin as well as several flavonoids interact in vitro with various amine receptors and transporters, showing that several substances in SJW are potential central nervous system psychoactive agents and may contribute to the antidepressant efficacy of the plant.18 However, HF is the main reuptake inhibitor, with half-maximal inhibitory concentrations for the synaptosomal uptakes of serotonin, norepinephrine and dopamine between 80 and 200 nmol/l.19
It was suggested that HF could affect a common point in the mechanism of action of the different transport proteins involved in the reuptake of these neurotransmitters. Indeed, HF reduced the sodium gradient used by these transporters as the driving force. Similar to monensin, the mode of action of HF seems to be associated with elevated intracellular sodium concentration [Na+]i.20 In addition to this activation of a sodium conductivity mechanism involving ionic channels, HF also stimulates the release of glutamate, aspartate and GABA from rat cortical synaptosomes as a consequence of an increase in their [Ca2+]i levels. Besides, HF decreased the pHi of synaptosomal suspension and prevented the generation of ATP-induced pH gradients of isolated synaptic vesicles.21 These observations suggest that the reuptake inhibitory properties of HF result from its effects on synaptosomal ionic homeostasis. The role of the enolized cyclohexanedione moiety in this process was highlighted by the observation that modification of HF by acylation, alkylation and oxidation resulted in detrimental effects on the inhibition of the synaptosomal accumulation of serotonin.22
Different non-mutually exclusive mechanisms of the ionic effects of HF have been reported. A role of amiloride-sensitive Na+ channels and Na+/H+ exchangers has been proposed to explain the reduction of the sodium gradient by HF and its inhibition of synaptosomal uptake of glutamate and GABA.23 HF interferes with the storage of monoamines in synaptic vesicles, rather than being a selective inhibitor of either synaptic membrane or vesicular monoamine transporters.24 HF seems to act by dissipating a pH gradient generated by an efflux of inwardly pumped protons induced by vacuolar-type H(+)-ATPase, which constitutes a major driving force for vesicular monoamines storage. HF also induces dose-dependent efflux of preloaded serotonin and dopamine from rat brain slices and attenuates their depolarization-dependent release. These data indicate that HF-induced efflux of serotonin and dopamine reflect elevated cytoplasmic concentrations of the two monoamines secondary to the depletion of the synaptic vesicle content and the redistribution of nerve ending monoamines.25
The reduction of the sodium gradient by HF was proposed to result from the opening of calcium channels.26 More recently, HF-induced elevation of [Na+]i was shown to be mediated by non-selective cation channels of the NSCC2 subclass, with a potential homology with canonical transient receptor potential protein channels.27
Additional neurological effects
Oral administration of SJW extract and of HF results in changes in brain membranes properties, such as decreased fluidity and increased acyl-chain flexibility,28 already observed in vitro. These data point out a membrane interaction of HF that possibly contributes to its pharmacological effects through an action on different ionic conductance mechanisms. HF inhibits smooth-muscle contraction induced by various neurotransmitters and this effect could also be linked to its capacity to stimulate elevation of [Ca2+]i and extracellular acidification independently of extracellular Ca2+.29
Avoidance tests suggest that Hypericum extract exhibits memory-enhancing properties, indicating that HF is involved in its cognitive effects, acting more as an antidementia agent than an antidepressant.30 HF also increases the release of acetylcholine from rat hippocampus in vivo in a calcium-dependent way, suggesting its potential therapeutic efficacy in central cholinergic dysfunction.31
HF stimulates the processing of the amyloid precursor protein (APP) in rat pheochromocytoma PC12 cells transfected with human wild-type APP, with a transiently increased release of secretory APP fragments and a strong reduction of intracellular APP.32 The formation of amyloid plaques in Alzheimer's disease patients results from an altered cleavage of APP by β- and γ-secretase that produce aggregable and neurotoxic β-amyloid peptides, in contrast with its processing by α-secretase. The data of Froestl et al.,32 indicating that HF stimulates preferentially α-secretase would suggest, if confirmed, a potential role of HF in the treatment of Alzheimer's disease.
Modulation of inflammation
SJW lipophilic extracts have been used for the topical treatment of superficial wounds, burns, scars and dermatitis.33 These anti-inflammatory effects are due, in part, to the inhibitory activity of quercetin on proinflammatory signal-transduction pathways, notably on the inducible nitric oxide synthase.12 HF plays a major role in this process by impairing the capacity of epidermal cells to stimulate T-cell activation and proliferation, providing a rationale for the traditional treatment of inflammatory skin lesions with SJW extracts.34 The same group has reported, in a randomized study, a superiority of HF in the topical treatment of mild to moderate atopic dermatitis.35
HF inhibits the oxidative burst of polymorphonuclear cells (PMNs) after stimulation with N-formyl-methionyl-leucyl-phenylalanine (fMLP), with a strong reduction of oxygen production.36 HF acts also as a dual inhibitor of 5-lipooxygenase, 5-LO, and of cyclooxygenase-1, COX-1, in intact cells as well as on the catalytic activity of the enzymes, suggesting therapeutic potential in inflammatory and allergic diseases connected to eicosanoids.37 These inhibitory effects might also contribute to the therapeutical indications of SJW and HF for the topical treatment of inflammatory skin lesions described above. HF inhibits the generation of reactive oxygen species and the release or activity of leukocyte elastase by human PMN stimulated with fMLP or platelet-activating factor (PAF), two molecules acting through G-protein-coupled receptors. HF appears to act by suppressing G-receptor-mediated calcium mobilization evoked by fMLP or PAF, suggesting that it targets component(s) of G-protein signaling cascades that regulate intracellular calcium concentration.38
On the other hand, HF induces interleukin-8 (IL-8) expression in human intestinal epithelial cells and hepatocytes.39 This induction is time- and dose-dependent and requires the stimulation of extracellular signal-regulated kinase 1 and 2, leading to the activation of the transcription factor AP-1. HF also induces intercellular adhesion molecule-1 (ICAM-1) mRNA.39 Both IL-8 and ICAM-1 are proinflammatory mediators, notably IL-8 that stimulates acute-phase protein production in the liver and contributes to intestinal inflammation. HF and HF-containing SJW extracts therefore display both anti- and proinflammatory activities, depending on their concentration and cell type. Thus, treatments with these agents need to be carefully controlled.
In agreement with early reports,6 HF was confirmed to display antibacterial activity against multiresistant Staphylococcus aureus and Gram-positive bacteria.40 HF exhibited an excellent effect against methicillin-resistant strains of S. aureus and Helicobacter pylori.41 HF and hypericin are also the major constituents of the growth inhibitory effect of SJW extracts against Bacillus subtilis and Bacillus cereus.42 The mechanisms involved are largely unknown.
HF and the clearance of xenobiotics
A restriction for the therapeutic use of SJW resides in the fact that these extracts interfere with the metabolism of other drugs. Unrecognized use of SJW is frequent among patients and may have an influence on the effectiveness of drug therapy during hospital stay. There is ample evidence that SJW may modulate two major systems controlling the uptake and elimination of xenobiotics by living cells, the cytochrome P450 (CYP40) enzymes system and the family of ABC drug transporters, leading possibly to a reduction in the efficacy of coadministered medications.43
SJW preparations contain constituents that inhibit several CYP450 drug-metabolizing enzymes.44 Again, HF is one of the major components responsible for this action, for instance, in the pharmacokinetic interaction between cyclosporin A and SJW.45 HF induces docetaxel metabolism, implying that subtherapeutic docetaxel concentrations may result when administered to patients using SJW on a chronic basis.46 The extent of CYP3A induction in patients receiving SJW derivatives was found to depend on their HF content.47 HF modulates differentially various CYP450 enzymes. In human hepatocytes cultures, whether it increases mRNA, protein and activity of CYP3A4 and CYP2C9, it has no effect on CYP1A2 or CYP2D6.48
This adverse effect of SJW on the metabolism of coadministered drugs results from the activation of the steroid X receptor (SXR), an orphan nuclear receptor that induces hepatic CYP450 gene expression in response to steroids, xenobiotics and drugs. HF mediates both transactivation and coactivator recruitment by SXR.49 HF is a ligand for another orphan nuclear receptor, the pregnane X receptor (PXR).50 PXR is involved in transcriptional regulation of multiple CYP450 and of MDR1 (multidrug resistance-associated protein) encoding the P-gp. PXR regulates the expression of CYP3A4 monooxygenase, an enzyme involved in the oxidative metabolism of more than 50% of all drugs. Moreover, HF-induced expression of the CYP2B6 gene occurs via a direct action of PXR on the phenobarbital-responsive enhancer module region of the CYP2B6 promoter, an enhancer element that also mediates induction of CYP2B6 expression by the constitutive androstane receptor or CAR.51 Through its interaction with PXR, HF mediates the induction of CYP2C952 and of CYP24, altering vitamin D3 hormonal activity and calcium homeostasis and leading ultimately to vitamin D deficiency or osteomalacia.53
SJW and HF regulate in a concordant way the expression of enzymes involved in basic cellular pathways in the hepatocyte HepG2 cell line. Both compounds increase mRNAs of various CYP and similarly affected expression of genes involved in energy metabolism, intracellular calcium regulation, cell proliferation and apoptosis.54
Several components of SJW extracts modulate the uptake and efflux of xenobiotics and drugs by members of the ABC transporters including P-gp.55 Both hypericin and HF inhibit the active efflux of the fluorescent markers daunorubicin and calcein.56 Similarly, SJW extracts, as well as quercetin and HF, modulate the transport by P-gp, suggesting the possibility of drug interactions at the level of the gastrointestinal absorption of drugs.57 Our group also observed that HF inhibited the activity of P-gp in various leukemias (Quiney et al. submitted). On the other hand, HF modulates the transcription of MDR1 through its effect on PXR, as mentioned previously. However, contradictory results have been published concerning the regulation of MDR-1/P-gp by HF. Patel et al.58 observed that HF caused a downregulation of MDR1 in human Caco-2 epithelial cells. In contrast, Tian et al.59 reported that SJW extracts and HF increased in a reversible way the expression and function of P-gp in the intestinal LS 180 cell line.
During the recent years, HF was shown, in addition, to exhibit antitumoral activity, as attested by its antiproliferative, proapoptotic, anti-invasive and antimetastasic effects.
Antiproliferative and proapoptotic effects
Alcoholic extracts of SJW induce dose-dependent growth arrest of several human malignant cells. Most experiments, however, have been performed with transformed cell lines, and it should be recalled that the sensitivity of normal and transformed cells can vary to a large extent. The leukemia cell lines K562 and U937 were the more sensitive and HF was suggested to be, at least partly, responsible for these effects.60 Indeed, purified HF inhibited the growth of these cells at GI(50) values about 12.5 μ M.61 Of note, these concentrations are rather high and may be cytotoxic in medium and long-term cultures. HF was reported to inhibit the growth of various other human and rat tumor cell lines in vivo and to elicit characteristic features of apoptosis in vitro.62 HF stimulated caspase-3 and -9 activity in MT-450 carcinoma cells and apoptosis was blocked by the caspase inhibitor zVAD.fmk. The intrinsic or mitochondrial pathway was involved, inasmuch as HF induced a dissipation of the mitochondrial transmembrane potential Δψm and the release of cytochrome c from mitochondria. HF treatment inhibited the growth of these cells in rats without any signs of acute toxicity.63 It is worth noting that other lipophilic compounds, in addition to HF, may be involved in apoptosis induction by SJW extracts in various cancer cells.64
Our group observed recently that HF displayed ex vivo proapoptotic activities in B-CLL patients' cells.1 HF elicited the externalization of phosphatidylserine, DNA fragmentation and dissipation of the transmembrane mitochondrial potential Δψm. HF stimulated caspase-3 activity and induced the caspase-dependent cleavage of poly-ADP ribose polymerase-1 and of two antiapoptotic proteins, Mcl-1 and Bcl-2. These two proteins are involved in the control of mitochondrial permeability and the release of apoptogenic molecules, and thus play important roles in the resistance of B-CLL cells to various chemotherapeutic agents. HF-induced apoptosis was associated with a downregulation of iNOS expression and of NO production by the leukemic cells. We showed previously that the endogenous production of NO by B-CLL cells is a component of their resistance to spontaneous apoptosis.65 This inhibition of the NO pathway could be a cause of apoptosis, inasmuch as HF-elicited apoptosis could be partially reverted by low concentrations of a NO donor. This would suggest that HF-induced suppression of NO release is a molecular switch contributing to subsequent apoptosis, perhaps through a release of the blocking effect of NO on the active site of caspases.66 We also observed that p27kip1, an inhibitor of cyclin-dependent kinase overexpressed in B-CLL, was downregulated by HF through a caspase-dependent pathway.1 The susceptibility of B-CLL to fludarabine in vitro is inversely correlated with p27kip1 levels, suggesting that this protein may be involved in the cell cycle arrest and in the resistance of patients to chemotherapy.67 By promoting the cleavage of p27kip1, HF could allow the cells to enter the cell cycle and therefore to become susceptible to a treatment with classical cell cycle-dependent chemotherapeutic agents.
Anti-invasive and antiangiogenic effects
Neo-angiogenesis, the formation of new blood vessels from the existing ones, plays a crucial role in the development of tumors by providing to cancer cells their necessary oxygen supply. Recent work has shown that HF displays both anti-invasive and antiangiogenic properties in vitro and in vivo. It was first reported that low concentrations of a dicyclohexylammonium salt of HF (DCHA-HF) inhibited the chemoinvasion of murine (C-26) and human (HT-1080) tumor cell lines through reconstituted basement membrane. The latter occured via the impairment of proteinases involved in extracellular matrix (ECM) degradation, elastase being inhibited to a much higher degree than cathepsin G and urokinase, and via a reduction in the secretion of matrix metalloproteinases 2 and 9 (MMP-2 and-9), two ECM remodeling enzymes. Daily intraperitoneal administration of 300 nmol of HF was shown to reduce the size and number of metastasis in two murine models of metastatic dissemination (C-26 and B16-LU8), with concomitant reduction of inflammatory infiltration and neovascularization.62 The anti-angiogenic properties of HF were confirmed by the observation that it inhibited the growth of endothelial cells in vitro, prevented the formation of capillary tubes by bovine aortic endothelial cells cultured on Matrigel and by the chorioallantoic membrane assay in vivo. HF also dramatically inhibited urokinase and MMP-2, two enzymes involved in the degradation of the basement membrane and of components of the ECM, an early step in the process of angiogenesis.68 HF also blocked microvessel formation of human dermal microvascular endothelial cells on ECM and reduced their proliferation in the absence of apoptosis induction.69 To evaluate the antiangiogenic activity of HF in vivo, peritumoral injections of HF in rats subcutaneously grafted with MT-450 mammary carcinoma cells were found to result in an inhibition of tumor growth, induction of apoptosis in tumor cells and reduced tumor vascularization. In addition to the induction of tumor cell apoptosis, HF can also suppress angiogenesis by a direct, non-toxic effect on endothelial cells.
Treatment of B-CLL cells with HF resulted in a marked inhibition of their capacity to secrete MMP-9, an essential component in the neo-angiogenesis through degradation of the ECM. The phloroglucinol impaired the production of the latent 92 kDa proenzyme and this was associated with a decrease in vascular endothelial growth factor release by the leukemic cells. Moreover, HF prevented the formation of micro-tubules by human bone marrow endothelial cells (HBMEC) cultured on Matrigel, evidencing its capacity to inhibit vessel formation.2 These results confirm the growing interest of HF as a potential drug for the treatment of cancer and the prevention of metastasis dissemination.
Reversal of P-gp activity
HF inhibits the functional activity of P-gp in B-CLL cells in vitro, as estimated by the enhanced uptake of rhodamine123. Similar effects were observed in a P-gp-overexpressing variant of the HL-60 cell line resistant to daunorubicin (Quiney et al., submitted). These results confirm that HF inhibits P-gp functional activity in vitro in different cell types. They suggest that HF could help revert the MDR phenotype and justify testing the pharmacological activity of this molecule in combination with classical chemotherapeutic agents.
As related previously, SJW extracts and HF modulate several enzymes of the CYP450 family, causing a risk of interference with the administration of other drugs. However, this modulation could be beneficial in some instances, inasmuch as SJW extracts and HF are potent inhibitors of carcinogen formation from benzo[a]pyrene-7,8-dihydrodiol by human CYP1A1, a major human procarcinogen-activating enzyme, HF acting as a competitive inhibitor.70 SJW and HF may therefore be worthy of further evaluation for cancer chemopreventive potential.
Pharmacology of HF
Using LC/MS/MS (liquid chromatography/tandem mass spectroscopy) technique, plasma levels of HF were followed for up to 24 h in healthy volunteers after the administration of tablets containing 300 mg hypericum extracts representing 14.8 mg HF. The maximum plasma levels (280 nM) were reached 3.5 h after administration and the half-life and mean residence time were 9 and 12 h, respectively. Plasma concentration curves in volunteers fitted well in an open two-compartment model and the estimated steady-state plasma concentrations of HF after 3 × 300 mg/day of the extract, that is, after normal therapeutic dose regimen, was approximately 180 nM.71 Other methods coupling solid-phase extraction and HPLC with UV detection or liquid chromatography-tandem mass spectrometry were used for the monitoring of HF concentration in plasma with comparable results.
Pharmacokinetic data for HF and other main constituents of hypericum extracts (hypericin, pseudohypericin, quercetin and isorhamnetin) were evaluated in open phase I clinical trials. These trials were performed in healthy male volunteers receiving single oral dose or multiple once daily dose over a period of 14 days. The following pharmacokinetic parameters for HF were determined: area under the curve [AUC (0–infinity)]=1550.4 h × ng/ml, maximum plasma concentration Cmax=122.0 ng/ml, time to reach Cmax (tmax)=4.5 h and elimination half-life (t1/2)=17.47 h. Similar results were obtained under steady-state conditions reached during multiple dose administration.72 Hydroxylation by CYP450 3A and/or CYP2B seems to be a major biotransformation of the HF pathway, as estimated by experiments performed with rat liver microsomes.73
Clinical studies have confirmed the efficacy and tolerability of SJW extracts in mild depressive disorders and the very low frequency of adverse events.74 Nowadays, most of the molecules responsible for the different biological activities present in these extracts have been identified and characterized, although some effects clearly result from synergistic action between several constituents. Among these components, HF displays multiple potential pharmacological uses and is the cause, not only of the antidepressant action of SJW but also of other neurological, anti-inflammatory, antibacterial, antiangiogenic and antitumoral effects. The lipophilic nature of HF allows this molecule to cross the plasma membrane of the cells. Little is known about the signaling pathways targeted by HF. They are probably multiple, inasmuch as HF exerts pleiotropic actions and the best characterized, so far, are the activation of several nuclear receptors, such as SXR and PXR. Obviously, unraveling the transduction pathways modulated by HF will be a major task in the next few years.
The use of HF as a new therapeutic agent is limited by its poor solubility and, above all, by its instability, mostly owing to is sensitivity to oxidation and heat. These limitations can, however, be circumvented by the use of different salts, which are much more stable and soluble in aqeous solutions. The acetate salt has been used with success in animal models sensitive to antidepressant and anxiolytic drugs.75 The DCHA-HF has been tested successfully for its antidepressant activity in rats.13 DCHA-HF has been recognized to trigger apoptosis in murine and human tumor cells and to reduce in vivo the number of metastasis in mice grafted with the C-26 and B16-LU8 tumors.62 DCHA-HF also inhibits the release of IL-6 by inflammatory mediators.54
Recently, a derivative of HF, the O-(carboxymethyl)-HF or aristoforin, has been synthesized. Aristoforin is highly stable, more soluble in aqueous solution than HF and retains the biological activities of the parental compound, notably the antitumor properties without inducing toxicity in experimental animals. This derivative displays strong inhibitory effect on the proliferation of MT-450 mammary carcinoma cells. Aristoforin has thus a great potential as an anticancer drug.76
Another major concern for HF pharmacological use resides in its potential interference with other drugs through its activating effect on various CYP450, notably CYP3A4.77 The design of HF analogs retaining the pharmacological properties of the parental compound, but unable to stimulate expression of CYP3A4 will be a challenge for the pharmacochemists in the near future.
Taking into account the antitumor activity of HF and its potential interest as a novel antineoplastic agent, this molecule certainly deserves thorough investigation.
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C Quiney was a recipient of a fellowship from the Société Française d'Hématologie. This work was supported by Canceropôle Ile-de-France.
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Quiney, C., Billard, C., Salanoubat, C. et al. Hyperforin, a new lead compound against the progression of cancer and leukemia?. Leukemia 20, 1519–1525 (2006). https://doi.org/10.1038/sj.leu.2404301
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