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Iqbal Ramzan - One of the best experts on this subject based on the ideXlab platform.
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kavain the major constituent of the anxiolytic kava extract potentiates gabaa receptors functional characteristics and molecular mechanism
PLOS ONE, 2016Co-Authors: Han Chow Chua, Emilie T H Christensen, Kirsten Hoestgaardjensen, Leonny Y Hartiadi, Nathan Absalom, Anders A Jensen, Iqbal Ramzan, Mary ChebibAbstract:Extracts of the pepper plant kava (Piper methysticum) are effective in alleviating anxiety in clinical trials. Despite the long-standing therapeutic interest in kava, the molecular target(s) of the pharmacologically active constituents, Kavalactones have not been established. γ-Aminobutyric acid type A receptors (GABAARs) are assumed to be the in vivo molecular target of Kavalactones based on data from binding assays, but evidence in support of a direct interaction between Kavalactones and GABAARs is scarce and equivocal. In this study, we characterised the functional properties of the major anxiolytic kavalactone, kavain at human recombinant α1β2, β2γ2L, αxβ2γ2L (x = 1, 2, 3 and 5), α1βxγ2L (x = 1, 2 and 3) and α4β2δ GABAARs expressed in Xenopus oocytes using the two-electrode voltage clamp technique. We found that kavain positively modulated all receptors regardless of the subunit composition, but the degree of enhancement was greater at α4β2δ than at α1β2γ2L GABAARs. The modulatory effect of kavain was unaffected by flumazenil, indicating that kavain did not enhance GABAARs via the classical benzodiazepine binding site. The β3N265M point mutation which has been previously shown to profoundly decrease anaesthetic sensitivity, also diminished kavain-mediated potentiation. To our knowledge, this study is the first report of the functional characteristics of a single kavalactone at distinct GABAAR subtypes, and presents the first experimental evidence in support of a direct interaction between a kavalactone and GABAARs.
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Chemical structures of the six major Kavalactones found in kava.
2016Co-Authors: Han Chow Chua, Emilie T H Christensen, Leonny Y Hartiadi, Nathan Absalom, Anders A Jensen, Iqbal Ramzan, Kirsten Hoestgaard-jensen, Mary ChebibAbstract:Chemical structures of the six major Kavalactones found in kava.
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Kavalactone metabolism in the isolated perfused rat liver.
Phytotherapy Research, 2012Co-Authors: Shuang Fu, Anthony Rowe, Iqbal RamzanAbstract:Metabolic pathways for kavalactone metabolism in humans and rats have been identified, but more detailed description of the enzyme kinetics involved is lacking. The disposition profiles of three of the six major Kavalactones (kavain, methysticin and desmethoxyyangonin) and their respective metabolites (p-hydroxykavain, m,p-dihydroxykavain and p-hydroxy-5,6-dehydrokavain) were examined in the perfusate and bile of the isolated perfused rat liver. The metabolism of the Kavalactones is first-order in nature with similar decay half-lives. p-Hydroxykavain and m,p-dihydroxykavain were the only metabolites detected in the perfusate. Kavalactone biliary excretion was negligible. Copyright © 2012 John Wiley & Sons, Ltd.
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Macrophage depletion ameliorates kavalactone damage in the isolated perfused rat liver.
The Journal of toxicological sciences, 2012Co-Authors: Lillian Y. Zhang, Filip Braet, Anthony Rowe, Iqbal RamzanAbstract:Liver toxicity is a side effect observed with some herbal treatments, including Piper methysticum. The possible mechanisms responsible include inflammation subsequent to activation of liver macrophages and oxidative damage. Hepatotoxicity of the pharmacologically active component of Piper methysticum (Kavalactones) was tested in isolated, perfused livers from rats which were pretreated with the macrophage intoxicant gadolinium chloride. Perfusions without Kavalactones in gadolinium chloride pretreated and untreated livers were included as negative controls. Serial liver lobe biopsies were collected to measure temporal changes in available (reduced) hepatic glutathione. There were no statistically significant changes in reduced glutathione over the course of perfusion in any experimental group. Liver damage was observed using electron microscopy. Hepatic sinusoids displayed extensive damage to the endothelium in kavalactone-perfused, rat livers. This damage was significantly reduced by pre-treatment with gadolinium chloride. Hence liver macrophages may be a factor in liver injury induced by Piper methysticum. Characterisation and modulation of the liver macrophage response may enable the development of strategies to avoid these hepatic side effects.
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Kavalactone Pharmacophores for Major Cellular Drug Targets
Mini reviews in medicinal chemistry, 2011Co-Authors: Anthony Rowe, Rajeshwar Narlawar, Paul W. Groundwater, Iqbal RamzanAbstract:A number of studies have identified differential kavalactone activity against a variety of molecular targets, including P-glycoprotein (Pgp), platelet monoamine oxidase (MAO-B), transcription factor binding domains, pregnane X (PXR) and GABA receptors, and cytochrome P450 and cyclo-oxygenase (COX) enzymes. The molecular structure of the Kavalactones possesses a pharmacophore for several of these targets. In most cases, conformational stability is more significant than the substituents present. The analysis of these pharmacophores provides important insights for future medicinal chemistry-based approaches to kavalactone-type drugs.
Kenneth J. Sufka - One of the best experts on this subject based on the ideXlab platform.
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Anxiolytic properties of Piper methysticum extract samples and fractions in the chick social-separation-stress procedure.
Phytotherapy research : PTR, 2003Co-Authors: Matt W. Feltenstein, N.p. Dhammika Nanayakkara, Ikhlas A. Khan, L. Corinne Lambdin, Markus Ganzera, H. Ranjith, W. Dharmaratne, Kenneth J. SufkaAbstract:Piper methysticum extract (Kava kava) possesses anxiolytic properties. However, it is unknown whether these effects are best predicted by total kavalactone content or by one or more of its primary kavalactone constituents. Using the chick social separation-stress procedure as an anxiolytic bioassay, P. methysticum samples containing 12.8-100.0% total Kavalactones (Exp. 1) and fractions containing 1-6 Kavalactones of varying concentrations (0.1-67.5%; Exps. 2-3) were screened for activity and compared against a 5.0 mg/kg dose of chlordiazepoxide (CDP; Exp. 3). Eight-day-old chicks received IP injections of either vehicle or test compounds 30 min before being placed in the presence of two conspecifics or in isolation for a 3 min observation period. Dependent measures were ventral recumbency latency (sedation), distress vocalizations, and a measure of stress-induced analgesia (in Exps. 1 and 2 only). P. methysticum extract samples attenuated distress vocalizations in a concentration-dependent manner. The P. methysticum fraction that contained the highest concentration of dihydrokavain attenuated distress vocalizations in a manner equivalent to that of CDP. The extract samples and fractions that possessed anxiolytic properties did not possess the sedative properties found in CDP. Collectively, these findings suggest that dihydrokavain may be necessary and sufficient in mediating the anxiolytic properties of P. methysticum extract.
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Anxiolytic effects of kava extract and Kavalactones in the chick social separation-stress paradigm
Psychopharmacology, 2001Co-Authors: Kenyatta K. Smith, Matt W. Feltenstein, Susan L. Broom, J. Todd Roach, H. Ranjith W. Dharmaratne, N.p. Dhammika Nanayakkara, Ikhlas A. Khan, Kenneth J. SufkaAbstract:Rationale: Piper methysticum extract (kava kava) possesses numerous therapeutic properties, but it is unknown which of its principle constituents (Kavalactones) subserve such effects. Objectives: This experiment sought to characterize the putative anxiolytic properties of P. methysticum extract and its six principle Kavalactones in the chick social separation-stress paradigm. Methods: Eight-day-old chicks received intraperitoneal injections of either vehicle, chlordiazepoxide (5.0 mg/ml per kg), P. methysticum extract (containing 30% Kavalactones), kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, or desmethoxyyangonin (30 mg/ml per kg for kava compounds) 30 min prior to being tested in the presence of two conspecifics or in isolation for a 3-min observation period. Latency to adopt a ventral recumbent posture to index sedation, number of vocalizations to index separation distress, and a composite pain score (in response to 50 µl 0.10% formalin injection into the plantar surface of the foot) to index stress-induced analgesia served as dependent measures. Results: Both chlordiazepoxide and P. methysticum extract attenuated separation-induced distress vocalizations and stress-induced analgesia. Dihydrokavain attenuated separation-induced distress vocalizations. Conclusions: These findings suggest that the anxiolytic effects of P. methysticum extract may be mediated, in part, by dihydrokavain.
Sophie Van Alphen - One of the best experts on this subject based on the ideXlab platform.
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Versatile asymmetric synthesis of the Kavalactones: first synthesis of (+)-kavain.
Organic Letters, 2004Co-Authors: Thomas E Smith, Mabel Djang, Alan J Velander, And Kathleen A Carroll, C. Wade Downey, Sophie Van AlphenAbstract:Three asymmetric pathways to the Kavalactones have been developed. The first method is chiral auxiliary-based and utilizes aldol reactions of N-acetyl thiazolidinethiones followed by a malonate displacement/decarboxylation reaction. The second approach uses the asymmetric catalytic Mukaiyama additions of dienolate nucleophile equivalents developed by Carreira and Sato. Finally, tin-substituted intermediates, prepared by either of these routes, can serve as advanced general precursors of kavalactone derivatives via Pd(0)-catalyzed Stille couplings with aryl halides.
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versatile asymmetric synthesis of the Kavalactones first synthesis of kavain
Organic Letters, 2004Co-Authors: Thomas E Smith, Mabel Djang, Alan J Velander, Wade C Downey, And Kathleen A Carroll, Sophie Van AlphenAbstract:Three asymmetric pathways to the Kavalactones have been developed. The first method is chiral auxiliary-based and utilizes aldol reactions of N-acetyl thiazolidinethiones followed by a malonate displacement/decarboxylation reaction. The second approach uses the asymmetric catalytic Mukaiyama additions of dienolate nucleophile equivalents developed by Carreira and Sato. Finally, tin-substituted intermediates, prepared by either of these routes, can serve as advanced general precursors of kavalactone derivatives via Pd(0)-catalyzed Stille couplings with aryl halides.
Vincent Lebot - One of the best experts on this subject based on the ideXlab platform.
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Comparison of kava (Piper methysticum Forst.) varieties by UV absorbance of acetonic extracts and high-performance thin-layer chromatography
Journal of Food Composition and Analysis, 2016Co-Authors: Vincent Lebot, Laurent LegendreAbstract:Abstract The development of quality standards to regulate the trade of kava ( Piper methysticum ) in the Pacific necessitates new analytical techniques for routine control of high-quality raw material. In the present study, varieties and parts of the plant were compared for their kavalactone and flavokavin (FK) profiles. Three hundred and eight samples corresponding to 25 noble, 25 two-days and five wichmannii varieties were collected from 203 different plants. Commercial samples were also analysed to test the technique. Overall, 353 samples were prepared (221 roots, 114 stumps, nine basal stems and nine stem peelings). Their acetonic extracts were measured for UV absorbance and analysed by HP-TLC. Two ratios were computed after scanning the plates at 245 nm (K/KL = kavain/total Kavalactones) and 366 nm (FK/KL = flavokavins/Kavalactones). The results indicate that noble varieties suitable for daily consumption of kava are characterised by high K/KL and low FK/KL. At 400 nm, the mean UV absorbance of acetonic extracts from noble, two-days and wichmannii varieties are 0.69, 0.94 and 1.04, respectively. The significant (+0.757**) correlation between the total FK content and the extracts absorbance at 400 nm indicates that a simple colorimeter can be used to detect poor-quality raw material.
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Proposal for a kava quality standardization code.
Food and Chemical Toxicology, 2011Co-Authors: Rolf Teschke, Vincent LebotAbstract:Rare cases of hepatotoxicity emerged with the use of kava drugs and dietary supplements prepared from rhizomes and roots of the South Pacific plant kava (Piper methysticum). Their psychoactive, anxiolytic, relaxing, and recreational ingredients are the Kavalactones kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, but there is little evidence that these Kavalactones or the non-Kavalactones pipermethystine and flavokavain B are the culprits of the adverse hepatic reactions. It rather appears that poor quality of the kava material was responsible for the liver toxicity. Analysis of existing kava quality standardizations with focus on chemical, agricultural, manufacturing, nutritional, regulatory, and legislation backgrounds showed major shortcomings that could easily explain quality problems. We therefore suggest a uniform, internationally accepted device for kava quality standardizations that are in the interest of the consumers because of safety reasons and will meet the expectations of kava farmers, pharmaceutical manufacturers, regulators of agencies, and legislators. The initial step resides in the establishment of Pan-Pacific kava quality legislation as an important part of the proposed Kava Quality Standardization Code. In conclusion, a sophisticated approach to establish kava quality standardizations is needed for safe human use of kava as relaxing traditional beverages, the anxiolytic drugs, and recreational dietary supplements.
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Kava and kava hepatotoxicity: requirements for novel experimental, ethnobotanical and clinical studies based on a review of the evidence.
Phytotherapy research : PTR, 2011Co-Authors: Rolf Teschke, Tran Dang Xuan, Samuel X. Qiu, Vincent LebotAbstract:Kava hepatotoxicity is a well described disease entity, yet there is uncertainty as to the culprit(s). In particular, there is so far no clear evidence for a causative role of Kavalactones and non-kavalactone constituents, such as pipermethystine and flavokavain B, identified from kava. Therefore, novel enzymatic, analytical, toxicological, ethnobotanical and clinical studies are now required. Studies should focus on the identification of further potential hepatotoxic constituents, considering in particular possible adulterants and impurities with special reference to ochratoxin A and aflatoxins (AFs) producing Aspergillus varieties, which should be urgently assessed and published. At present, Aspergillus and other fungus species producing hepatotoxic mycotoxins have not yet been examined thoroughly as possible contaminants of some kava raw materials. Its occurence may be facilitated by high humidity, poor methods for drying procedures and insufficient storage facilities during the time after harvest. Various experimental studies are recommended using aqueous, acetonic and ethanolic kava extracts derived from different plant parts, such as peeled rhizomes and peeled roots including their peelings, and considering both noble and non-noble kava cultivars. In addition, ethnobotanical studies associated with local expertise and surveillance are required to achieve a good quality of kava as the raw material. In clinical trials of patients with anxiety disorders seeking herbal anxiolytic treatment with kava extracts, long-term safety and efficacy should be tested using traditional aqueous extracts obtained from peeled rhizomes and peeled roots of a noble kava cultivar, such as Borogu, to evaluate the risk: benefit ratio. Concomitantly, more research should be conducted on the bioavailability of Kavalactones and non-Kavalactones derived from aqueous kava extracts. To be on the side of caution and to ensure lack of liver injury, kava consuming inhabitants of the kava producing or importing South Pacific islands should undergo assessment of their liver function values and serum aflatoxin levels. The primary aim is to achieve a good quality of kava raw material, without the risk of adulterants and impurities including ochratoxin A and AFs, which represent the sum of aflatoxin B1, B2, G1 and G2. Although it is known that kava may naturally be contaminated with AFs, there is at present no evidence that kava hepatotoxicity might be due to aflatoxicosis. However, appropriate studies have yet to be done and should be extended to other mould hepatotoxins, with the aim of publishing the obtained results. It is hoped that with the proposed qualifying measures, the safety of individuals consuming kava will substantially be improved. Copyright © 2011 John Wiley & Sons, Ltd.
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Identification of factors determining kavalactone content and chemotype in Kava (Piper methysticum Forst. f.)
Biochemical Systematics and Ecology, 2002Co-Authors: Patricia Siméoni, Vincent LebotAbstract:This study presents results of field experiments conducted to identify factors determining kavalactone content and chemotype in Piper methysticum. The following factors have been studied: (1) the geographical direction of the roots on the plant, (2) the geographical location of the plant, (3) its age, and (4) its organ (roots, stumps, or basal stems). Overall, 185 samples were analysed by HPLC. It appears that the geographical direction of the roots (North, East, South, West) is not significant. Chemotype and kavalactone content variation among clones of a cultivar grown in a common garden is negligible. There is significant variation among different cultivars originating from the same island. The variation within island is comparable to the variation existing within the whole Vanuatu archipelago. For a given cultivar, chemotype is stable across locations. There are however, chemotype differences between organs. Kavalactone content is always higher in the roots than in the stumps and higher in the stumps than in the basal stems. Experimental data obtained from one cultivar indicate that at the juvenile stage (less than 18 months of growth), kavalactone content is still low but increasing progressively: from 3% of dry matter at 10 months to 8% at 17 months. After two years of vegetative growth, the chemotype appears stable and kavalactone content does not increase but rather fluctuates (±2%). Although seasonal factors might have an effect, it is not possible to observe a significant trend. It is confirmed that chemotype is genetically controlled. However, kavalactone content appears to be greatly determined by the growing conditions, either by the local environment or by the agricultural techniques used by the local farmers. Consequently, the selection of the cultivar, its organ and the geographical area of origin are factors contributing directly to quality control in Piper methysticum.
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Morphological, phytochemical, and genetic variation in hawaiian cultivars of ’Awa (Kava,Piper methysticum, piperaceae)
Economic Botany, 1999Co-Authors: Vincent Lebot, Ed Johnston, Doug Mckern, Qunyi Zheng, Dennis J. MckennaAbstract:Standardized morphological descriptions, quantitative phytochemical analyses (HPLC) of major Kavalactones and DNA fingerprinting (AFLP) were utilized to define the extent of variation existing between Hawaiian cultivars of Piper methysticum. For each cultivar, morphotypes and chemotypes were compared to their respective genotypes. Overall, 63 samples were analyzed for their kavalactone content and composition (44 root samples, 6 stump, 5 basal stem, 7 leaves and 1 peelings). Results obtained from different cultivars planted in an homogeneous environment (soil and climate) are quite variable for the kavalactone content of their roots. Total kavalactone content decreases when shade increases over the plants. Total kavalactone content markedly increases with fertility, irrigation and in a cultivated type of habitat. However, kavalactone content appears to be independent of the age of the plant. For all cultivars analyzed, total kavalactone content decreases from the roots to the stump; the basal stems and the leaves exhibit the lower concentration. It is also observed that there is a correlation between the total kavalactone content and the size of the roots: smaller roots tend to have a higher kavalactone content. Peelings of the bark had a higher kavalactone content than the stump and represent a very interesting by-product for the extraction industry. Chemotypes are similar in the roots and the stump, while they differ in the aerial parts where the concentrations in dihydrokavain and dihydromethysticin increase. DNA samples were extracted from fresh leaves collected on 22 accessions. Most accessions, representing all Hawaiian morphotypes were monomorphs for the 21 pairs of primers assayed. Kava in Hawai’i is a species with an extremely narrow genetic base. Morphological and phytochemical variation is obviously controlled by very few genes. Most cultivars representing different morphotypes are most likely somatic mutants from a common clonal source introduced by Polynesians during early settlements.
Zhongbo Liu - One of the best experts on this subject based on the ideXlab platform.
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Kavalactone yangonin induces autophagy and sensitizes bladder cancer cells to flavokawain A and docetaxel via inhibition of the mTOR pathway
Journal of biomedical research, 2017Co-Authors: Zhongbo Liu, Noriko YokoyamaAbstract:Consumption of kava (Piper methysticum Forst) has been linked to reduced cancer risk in the South Pacific Islands. Kavalactones are major bioactive components in kava root extracts, which have recently demonstrated anti-cancer activities. However, molecular mechanisms of Kavalactones' anti-cancer action remain largely unknown. We have identified two Kavalactones, yangonin and 5' 6'-dehydrokawain, as potent inducers of autophagic cell death in bladder cancer cells. The effect of yangonin inducing autophagy is associated with increased expression of beclin and ATG5. In addition, yangonin increases the expression of LKB1 and decreases the phosphorylation of Akt, PRAS40, rpS6, p70S6K and 4E-BP1, leading to increased binding of 4E-BP1 to m7 GTP. The growth inhibitory effects of yangonin were attenuated inTSC1 or LKB1 knockout mouse embryonic fibroblasts, suggesting that TSC1 and LKB1 expression may contribute to optimal growth inhibition by yangonin. Furthermore, yangonin reduces the viability of bladder cancer cell lines derived from different stages of human bladder cancer, and acts synergistically with apoptosis-inducing agents such as docetaxel and flavokawain A. Our results support a novel anti-bladder cancer mechanism by yangonin and further studies are needed to assess the potential use of yangonin for bladder cancer prevention and treatment.
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Kava Components Down-Regulate Expression of AR and AR Splice Variants and Reduce Growth in Patient-Derived Prostate Cancer Xenografts in Mice
2016Co-Authors: Zhongbo Liu, Christopher A. Blair, Zheng Sun, Jun Xie, Michael B. LillyAbstract:Men living in Fiji and drinking kava have low incidence of prostate cancer (PCa). However, the PCa incidence among Fijian men who had migrated to Australia, increased by 5.1-fold. We therefore examined the potential effects of kava root extracts and its active components (Kavalactones and flavokawains) on PCa growth and androgen receptor (AR) expression. PCa cell lines (LNCaP, LAPC-4, 22Rv1, C4-2B, DU145 and PC-3) with different AR expression, and a transformed prostate myofibroblast cell line (WPMY-1), were treated with a commercial kava extract, Kavalactones (kawain, 5969-dehydrokawain, yangonin, methysticin) and flavokawain B. Expression of AR and its target genes (PSA and TMPRSS2) was examined. Two novel patient-derived PCa xenograft models from high grade PCa specimens were established by implanting the specimens into nude mice and passing tumor pieces through subcutaneous injection in nude mice, and then treated with kava extract and flavokawain B to examine their effects on tumor growth, AR expression and serum PSA levels. The kava extract an
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UPLC analysis of Kavalactones and flavokawain B in the kava root extract.
2013Co-Authors: Zhongbo Liu, Christopher A. Blair, Zheng Sun, Jun Xie, Michael B. LillyAbstract:UPLC analysis of Kavalactones and flavokawain B in the kava root extract.
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Abstract 2588: The effect of kava extracts and Kavalactones on histone lysine methylation in urinary bladder cancer
Prevention Research, 2012Co-Authors: Xuejiao Tian, Shuman Liu, Zhongbo LiuAbstract:According to the GLOBOCAN08, Cancer Incidence and Mortality Worldwide in 2008 report, age-standardized incidences of tobacco-smoking related lung and bladder cancers in three kava drinking pacific countries (Fiji, Vanutu and Samoa) were markedly lower than those in their neighbor countries, such as Australia and New Zealand, despite of the higher percentages of smokers in their populations (up to 58.3% of man in Samoa smoke). It has recently been thought that modification of reversible epigenetic events such as histone acetylation and methylation during carcinogenesis may be one of the most promising ways in prevention of tobacco-smoking related cancers. We therefore examined the effect of kava extracts and their main chemical components Kavalactones on histone lysine methylation in malignant and non-malignant bladder cell lines. Our data have shown that the kava crude extract, kawain and methysticin but not dehydrokawain, yangonin, 11-methoxyyangonin in the extract induce expression of H3K4 me1 and me2, as well as H3K9 me2 in bladder cancer cell lines (5637, T24 and RT4). In addition, both kawain and methysticin significantly inhibits the in vitro activity of demethylase lysine-specific demethylase 1 (LSD1). Compared to non-malignant bladder epithelial cells TEU2, bladder cancer cells express very little or no H3K4 me1 and me2, as well as H3K9 me2. Among all the tested Kavalactones, kawain demonstrated selectivity in inhibition of the growth of bladder cancer cells versus non-malignant bladder epithelial cells (TEU2). Consistent with the above results, a specific LSD1 inhibitor II and a nonspecific monoamine oxidases inhibitor trans-2-Phenylcyclopropylamine (2-PCPA, also known to inhibit LSD1) significantly induce the expression of H3K4 me1 and me2, as well H3K9me2 in tested bladder cancer cell lines. Furthermore, dietary feeding of 6 g kawain/kg mouse food significantly slows down hydroxybutyl(butyl)nitrosamine (OH-BBN)-induced mouse urinary bladder carcinogenesis and increases the survival rates of mice treated with OH-BBN in both prevention (kawain was given before the OH-BBN treatment) and promotion (kawain was given after the OH-BBN treatment) protocols. Immunohistochemistry on paraffin-embedded bladder sections revealed that OH-BBN-induced mouse bladder tumors show significantly decreased H3K4me1 expression (p=0.0005) compared to normal mouse bladders, whereas bladder tissues from kawain treated mice show a significant increase in the expression of H3K4me1 compared to those from vehicle control treated mice in the OH-BBN model (p=0.002). Taken together, our results suggested that modification of histone lysine methylation may represent a new approach for bladder cancer prevention and treatment, and that kavalacones may be promising cancer preventive agents existing in the kava plant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2588. doi:1538-7445.AM2012-2588
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Kava Components Down-Regulate Expression of AR and AR Splice Variants and Reduce Growth in Patient-Derived Prostate Cancer Xenografts in Mice
PloS one, 2012Co-Authors: Zhongbo Liu, Christopher A. Blair, Zheng Sun, Jun Xie, Michael B. LillyAbstract:Men living in Fiji and drinking kava have low incidence of prostate cancer (PCa). However, the PCa incidence among Fijian men who had migrated to Australia, increased by 5.1-fold. We therefore examined the potential effects of kava root extracts and its active components (Kavalactones and flavokawains) on PCa growth and androgen receptor (AR) expression. PCa cell lines (LNCaP, LAPC-4, 22Rv1, C4-2B, DU145 and PC-3) with different AR expression, and a transformed prostate myofibroblast cell line (WPMY-1), were treated with a commercial kava extract, Kavalactones (kawain, 5′6′-dehydrokawain, yangonin, methysticin) and flavokawain B. Expression of AR and its target genes (PSA and TMPRSS2) was examined. Two novel patient-derived PCa xenograft models from high grade PCa specimens were established by implanting the specimens into nude mice and passing tumor pieces through subcutaneous injection in nude mice, and then treated with kava extract and flavokawain B to examine their effects on tumor growth, AR expression and serum PSA levels. The kava extract and flavokawain B effectively down-regulated the expression of both the full-length AR and AR splice variants. The kava extract and Kavalactones accelerated AR protein degradation, while flavokawain B inhibited AR mRNA transcription via decreasing Sp1 expression and the binding of Sp1 to the AR promoter. The kava root extract and flavokawain B reduce tumor growth, AR expression in tumor tissues and levels of serum PSA in the patient-derived PCa xenograft models. These results suggest a potential usefulness of a safe kava product or its active components for prevention and treatment of advanced PCa by targeting AR.