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Effects of Garcinol from Kokum (Garcinia indica) on the Prevention and Treatment of Cancer

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Abstract

Kokum (Garcinia indica) has been applied for dishes of the Konkan region of Western India for centuries. There is growing evidence that its major ingredients like hydroxycitric acid (HCA) and garcinol have beneficial health effects. While HCA is considered to be a suitable tool to manage obesity, the polyisoprenylated benzophenone garcinol has revealed potent anticancer, antibacterial, anti-inflammatory, and anti-ulcer effects. This chapter provides an overview of the latest developments of garcinol and its derivatives concerning the prevention and treatment of various cancer diseases. After a short introduction, important chemical aspects of garcinol are discussed followed by an overview of inflammation-related targets of garcinol such as NF-κB, 5-LOX, and STAT proteins playing also a big role in cancer progression. Interference of chromatin regulation and HAT substrate stability by the HAT inhibitor garcinol and a final comment on the anti-ulcer activity of garcinol complete this chapter. Pertinent literature is covered up to 2014.

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... This compound and analogs, such as isogarcinol, inhibit the activity of HATs, mainly KAT2B and EP300. Overall, they are capable of modulating gene transcription by HAT activity-dependent chromatin [82,99]. The inhibitory mechanism of garcinol likely involves alterations in the ordered segment of the secondary structure of these HATs [100]. ...
... The inhibitory mechanism of garcinol likely involves alterations in the ordered segment of the secondary structure of these HATs [100]. Furthermore, the inhibition of KAT2B and EP300 reduces the levels of acetylation and impacts the function/stability of nonhistone proteins that serve as substrates, such as STAT-3, FOXP3, NF-kB/p65 and p53 [82]. ...
... Moreover, garcinol influences some crucial signaling pathways that induce apoptosis [81,82,99]. A previous study showed that garcinol favors the activation of caspases 2 and 3, procaspase-9 processing, the release of cytochrome C into the cytosol, the degradation of poly (ADP-ribose) polymerase (PARP), and DNA fragmentation caused by caspase-activated deoxyribonuclease [101]. ...
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Histone modifications regulate the structural status of chromatin and thereby influence the transcriptional status of genes. These processes are controlled by the recruitment of different enzymes to a specific genomic site. Furthermore, obtaining an understanding of these mechanisms could help delineate alternative treatment and preventive strategies for cancer. For example, in gastric cancer, cholecalciferol, curcumin, resveratrol, quercetin, garcinol and sodium butyrate are natural regulators of acetylation and deacetylation enzyme activity that exert chemopreventive and anticancer effects. Here, we review the recent findings on histone acetylation in gastric cancer and discuss the effects of nutrients and bioactive compounds on histone acetylation and their potential role in the prevention and treatment of this type of cancer.
... [24,25] Both garcinol and isogarcinol showed a plethora of biological activities against cancer, infections, and inflammatory diseases. [26,27] The activities of garcinol against various in vivo tumor models were thoroughly investigated and the compound was well tolerated by laboratory animals at active doses. [28][29][30] In addition, garcinol was identified as a natural histone acetyltransferase (HAT) inhibitor and it suppressed the lysine acetylation of the influenza A viral nucleoprotein. ...
... Garcinol (camboginol) was isolated from dried kokum plums as a yellow solid according to literature procedures. [26] The dried kokum plums (500 g) were chopped, methanol (1 L) was added to the chopped plums, and the suspension was stirred with a KPG stirrer at room temperature for 24 h. ...
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The bioactive components of Garcinia indica, garcinol (camboginol), and isogarcinol (cambogin), are suitable drug candidates for the treatment of various human diseases. HIV-1-RNase H assay was used to study the RNase H inhibition by garcinol and isogarcinol. Docking of garcinol into the active site of the enzyme was carried out to rationalize the difference in activities between the two compounds. Garcinol showed higher HIV-1-RNase H inhibition than the known inhibitor RDS1759 and retained full potency against the RNase H of a drug-resistant HIV-1 reverse transcriptase form. Isogarcinol was distinctly less active than garcinol, indicating the importance of the enolizable β-diketone moiety of garcinol for anti-RNase H activity. Docking calculations confirmed these findings and suggested this moiety to be involved in the chelation of metal ions of the active site. On the basis of its HIV-1 reverse transcriptase-associated RNase H inhibitory activity, garcinol is worth being further explored concerning its potential as a cost-effective treatment for HIV patients.
... [24,25] Both garcinol and isogarcinol showed a plethora of biological activities against cancer, infections, and inflammatory diseases. [26,27] The activities of garcinol against various in vivo tumor models were thoroughly investigated and the compound was well tolerated by laboratory animals at active doses. [28][29][30] In addition, garcinol was identified as a natural histone acetyltransferase (HAT) inhibitor and it suppressed the lysine acetylation of the influenza A viral nucleoprotein. ...
... Garcinol (camboginol) was isolated from dried kokum plums as a yellow solid according to literature procedures. [26] The dried kokum plums (500 g) were chopped, methanol (1 L) was added to the chopped plums, and the suspension was stirred with a KPG stirrer at room temperature for 24 h. ...
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Full-text available
The bioactive components of Garcinia indica, garcinol (camboginol), and isogarcinol (cambogin), are suitable drug candidates for the treatment of various human diseases. HIV-1-RNase H assay was used to study the RNase H inhibition by garcinol and isogarcinol. Docking of garcinol into the active site of the enzyme was carried out to rationalize the difference in activities between the two compounds. Garcinol showed higher HIV-1-RNase H inhibition than the known inhibitor RDS1759 and retained full potency against the RNase H of a drug-resistant HIV-1 reverse transcriptase form. Isogarcinol was distinctly less active than garcinol, indicating the importance of the enolizable β-diketone moiety of garcinol for anti-RNase H activity. Docking calculations confirmed these findings and suggested this moiety to be involved in the chelation of metal ions of the active site. On the basis of its HIV-1 reverse transcriptase-associated RNase H inhibitory activity, garcinol is worth being further explored concerning its potential as a cost-effective treatment for HIV patients.
... The antioxidant properties of garcinol may be attributed to its β-diketone and catechol fragments in its structure [80]. In response to garcinol the free radicals get converted ( Figure 4) to derivatives like garcim-2, isogarcinol, xanthone derivative gatcim-1, and hydroperoxide metabolite to neutralize oxidative stress caused by them [53,81,82]. ...
... In a study, garcinol exhibited the reduced tumorigenic cell proliferation in human pancreatic BxPC-3 cell lines (IC 50 value of 20 µM) and human lung carcinoma cell lines (IC 50 value of 10 µM) by inhibiting downstream synthesis of prostanoid and COX-2 expression [91,92]. The antioxidant properties of garcinol may be attributed to its β-diketone and catechol fragments in its structure [80]. In response to garcinol the free radicals get converted ( Figure 4) to derivatives like garcim-2, isogarcinol, xanthone derivative gatcim-1, and hydroperoxide metabolite to neutralize oxidative stress caused by them [53,81,82]. ...
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Garcinol, a polyisoprenylated benzophenone, is the medicinal component obtained from fruits and leaves of Garcinia indica (G. indica) and has traditionally been extensively used for its antioxidant and anti-inflammatory properties. In addition, it has been also been experimentally illustrated to elicit anti-cancer properties. Several in vitro and in vivo studies have illustrated the potential therapeutic efficiency of garcinol in management of different malignancies. It mainly acts as an inhibitor of cellular processes via regulation of transcription factors NF-κB and JAK/STAT3 in tumor cells and have been demonstrated to effectively inhibit growth of malignant cell population. Numerous studies have highlighted the anti-neoplastic potential of garcinol in different oncological transformations including colon cancer, breast cancer, prostate cancer, head and neck cancer, hepatocellular carcinoma, etc. However, use of garcinol is still in its pre-clinical stage and this is mainly attributed to the limitations of conclusive evaluation of pharmacological parameters. This necessitates evaluation of garcinol pharmacokinetics to precisely identify an appropriate dose and route of administration, tolerability, and potency under physiological conditions along with characterization of a therapeutic index. Hence, the research is presently ongoing in the dimension of exploring the precise metabolic mechanism of garcinol. Despite various lacunae, garcinol has presented with promising anti-cancer effects. Hence, this review is motivated by the constantly emerging and promising positive anti-cancerous effects of garcinol. This review is the first effort to summarize the mechanism of action of garcinol in modulation of anti-cancer effect via regulation of different cellular processes.
... Chemically, garcinol (camboginol) is a type B polycyclic polyprenylated acylphloroglucinol (PPAP) featuring a benzophenone derivative with five isoprenyl side chains attached to the phloroglucinol core (Fig. 1) [117]. Garcinol is easily isolated from dried kokum plums, however, there's a total synthetic procedure of garcinol and its close congener isogarcinol available now as well [118,119]. The chemical structure of garcinol shows some similarities with curcumin (b-diketone, phenol). ...
... The chemical structure of garcinol shows some similarities with curcumin (b-diketone, phenol). Garcinol has revealed significant anticancer activity by targeting NF-kB, 5- lipoxygenase (5-LOX), and STAT proteins (for a recent review see ref. [118]). In addition, garcinol is a well-documented HAT inhibitor (histone acetylase inhibitor) and, thus, plays an important role for the epigenetic regulation of gene expression including the expression of oncogenes [120]. ...
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... The activity method for the apoptosis or cell death by caspase actuated apoptosis in G0/G1 and S stages individually that aids in decreasing ROS levels [90]. In a new study, a polyphenol from kokum fruits was extracted and given in the form of encapsulated nanoparticles to the breast cancer mice with B16F10 melanoma tumor as in vivo study at the concentration of 50 to 100 µM via tail vein resulted in the active target of a tumor to muscle to blood reachability within 8 h of injection [91]. ...
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Garcinol, harvested from Garcinia indica, has traditionally been used in tropical regions and appreciated for centuries; however its biological properties are only beginning to be elucidated. There is ample data to suggest potent antioxidant properties of this compound which have been used to explain most of its observed biological activities. However, emerging evidence suggests that garcinol could be useful as an anti-cancer agent, and it is increasingly being realized that garcinol is a pleiotropic agent capable of modulating key regulatory cell signaling pathways. Here we have summarized the progress of our current research knowledge on garcinol and its observed biological activities. We have also provided an explanation of observed properties based on its chemical structure and provided an insight into the structure and properties of chalcones, the precursors of garcinol. The available data is promising but more detailed investigations into the various properties of this compound, particularly its anti-cancer activity are urgently needed, and it is our hope that this review will stimulate further research for elucidating and appreciating the value of this nature's wonder agent.
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Whether garcinol, the active component of Garcinia indica, can modulate the sensitivity of cancer cells to TRAIL, a cytokine currently in phase II clinical trial, was investigated. We found that garcinol potentiated TRAIL-induced apoptosis of cancer cells as indicated by intracellular esterase activity, DNA strand breaks, accumulation of the membrane phospholipid phosphatidylserine, mitochondrial activity, and activation of caspase-8, -9, and -3. We found that garcinol, independent of the cell type, induced both of the TRAIL receptors, death receptor 4 (DR4) and DR5. Garcinol neither induced the receptors on normal cells nor sensitized them to TRAIL. Deletion of DR5 or DR4 by small interfering RNA significantly reduced the apoptosis induced by TRAIL and garcinol. In addition, garcinol downregulated various cell survival proteins including survivin, bcl-2, XIAP, and cFLIP, and induced bid cleavage, bax, and cytochrome c release. Induction of death receptors by garcinol was found to be independent of modulation of CCAAT/enhancer-binding protein-homologous protein, p53, bax, extracellular signal-regulated kinase, or c-Jun-NH(2)-kinase. The effect of garcinol was mediated through the generation of reactive oxygen species, in as much as induction of both death receptors, modulation of antiapoptotic and proapoptotic proteins, and potentiation of TRAIL-induced apoptosis were abolished by N-acetyl cysteine and glutathione. Interestingly, garcinol also converted TRAIL-resistant cells into TRAIL-sensitive cells. Overall, our results indicate that garcinol can potentiate TRAIL-induced apoptosis through upregulation of death receptors and downregulation of antiapoptotic proteins. Mol Cancer Ther; 9(4); 856-68. (c)2010 AACR.
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Our understanding of the molecular mechanisms that link inflammation and cancer has significantly increased in recent years. Here, we analyse genetic evidence indicating that the transcription factors nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) have a central role in this context by regulating distinct functions in cancer cells and surrounding non-tumorigenic cells. In immune cells, NF-kappaB induces the transcription of genes that encode pro-inflammatory cytokines, which can act in a paracrine manner on initiated cells. By contrast, in tumorigenic cells, both NF-kappaB and STAT3 control apoptosis, and STAT3 can also enhance proliferation. Consequently, inflammation should be considered as a valuable target for cancer prevention and therapy.
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Polyprenylated acylphloroglucinols (PPAPs) are structurally complex natural products with promising biological activities. Herein, we present a biosynthesis-inspired, diversity-oriented synthesis approach for rapid construction of PPAP analogs via double decarboxylative allylation (DcA) of acylphloroglucinol scaffolds to access allyl-desoxyhumulones followed by dearomative conjunctive allylic alkylation (DCAA).
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The acetyltransferase inhibitor garcinol, a polyisoprenylated benzophenone, is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Anti-cancer activity has been suggested but there is no report on its action via inhibiting acetylation against cell proliferation, cell cycle progression, and apoptosis-inhibtion induced by estradiol (E2) in human breast cancer MCF-7 cells. The main purposes of this study were to investigate the effects of the acetyltransferase inhibitor garcinol on cell proliferation, cell cycle progression and apoptosis inhibition in human breast cancer MCF-7 cells treated with estrogen, and to explore the significance of changes in acetylation levels in this process. We used a variety of techniques such as CCK-8 analysis of cell proliferation, FCM analysis of cell cycling and apoptosis, immunofluorescence analysis of NF-κB/ p65 localization, and RT-PCR and Western blotting analysis of ac-H3, ac-H4, ac-p65, cyclin D1, Bcl-2 and Bcl- xl. We found that on treatment with garcinol in MCF-7 cells, E2-induced proliferation was inhibited, cell cycle progression was arrested at G0/G1 phase, and the cell apoptosis rate was increased. Expression of ac-H3, ac-H4 and NF-κB/ac-p65 proteins in E2-treated MCF-7 cells was increased, this being inhibited by garcinol but not ac- H4.The nuclear translocation of NF-κB/p65 in E2-treated MCF-7 cells was also inhibited, along with cyclin D1, Bcl-2 and Bcl-xl in mRNA and protein expression levels. These results suggest that the effect of E2 on promoting proliferation and inhibiting apoptosis is linked to hyperacetylation levels of histones and nonhistone NF-κB/ p65 in MCF-7 cells. The acetyltransferase inhibitor garcinol plays an inhibitive role in MCF-7 cell proliferation promoted by E2. Mechanisms are probably associated with decreasing ac-p65 protein expression level in the NF-κB pathway, thus down-regulating the expression of cyclin D1, Bcl-2 and Bcl-xl.
Article
Scope: Garcinol is a polyisoprenylated benzophenone derivative isolated from the fruit rind of Garcinia indica and has exhibited chemopreventive effects on azoxymethane)-induced colonic aberrant crypt foci in mice. In this study, we investigated whether garcinol protects against dextran sulfate sodium (DSS) induced colitis/inflammation and azoxymethane/DSS-induced inflammation-related colon tumorigenesis in male ICR mice. We also aimed to delineate the possible molecular mechanisms responsible for these effects. Methods and results: Treatment with garcinol prevented shortening of the colon length and the formation of aberrant crypt foci and improved the inflammation score in the mouse colon stimulated by DSS. Moreover, administration of garcinol markedly decreased DSS-induced inducible nitric oxide synthase, cyclooxygenase-2, and proliferating cell nuclear antigen protein expression. The dietary administration of garcinol effectively reduced the tumor size and incidence in the mouse colon. Western blot and immunohistochemical analysis revealed that administration of garcinol significantly downregulated cyclooxygenase-2, cyclin D1, and vascular endothelial growth factor expression via inhibition of the extracellular signal-regulated protein kinase 1/2, phosphatidylinositol 3 kinase/Akt/p70 ribosomal S6 kinase, and Wnt/β-catenin signaling pathways. Conclusion: Our results suggest that garcinol may merit further clinical investigation as a chemoprophylactic food that helps prevent colitis-associated colon cancer.
Article
Garcinol (1), a polyisoprenylated benzophenone, purified from Garcinia indica fruit rind, displays antioxidant properties and is thought to act as an antioxidant in biological systems. However, the mechanisms of its antioxidant reactions remain unknown. The objective of this study was to characterize the reaction products of garcinol with a stable radical, 2,2-diphenyl-1-picrylhydrazyl (DPPH). Structural elucidation of these products can provide insights into specific mechanisms of antioxidant reactions. Two major reaction products, GDPPH-1 (2) and GDPPH-2 (3), were isolated and identified for the first time. Their structures were determined on the basis of detailed high field 1D and 2D spectral analysis. The identification of these products provides the first unambiguous proof that the principal sites of antioxidant reactions are on the 1,3-diketone and the phenolic ring part of 1. The induction of apoptosis in human leukemia HL-60 cells, the inhibition of NO generation, the effects on the activity of MMP, and the inhibitory effects on H2O2 production of TPA-stimulate HL-60 cells by 1 and its two oxidant products (2 and 3) were investigated and would also be discussed in this paper.
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We report a stereodivergent, asymmetric total synthesis of (-)-clusianone in six steps from commercial materials. We implement a challenging cationic cyclization forging a bond between two sterically encumbered quaternary carbon atoms. Mechanistic studies point to the unique ability of formic acid to mediate the cyclization forming the clusianone framework. Aim for selectivity: (-)-Clusianone was produced by a stereodivergent asymmetric total synthesis in six steps from commercial materials. The synthesis utilizes a challenging formic acid-mediated cationic cyclization forging a bond between two sterically encumbered quaternary carbon atoms.
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Isogarcinol is a natural compound that we extracted from Garcinia mangostana Linn, and we were the first to report that it is a new immunosuppressant. In the present study, we investigated the immune-regulation and anti-inflammatory effects of isogarcinol on collagen-induced arthritis (CIA) and explored its potential mechanism in the treatment of rheumatoid arthritis. The oral administration of isogarcinol significantly reduced clinical scores, alleviated cartilage and bone erosion and reduced the levels of serum inflammatory cytokines in CIA mice. Isogarcinol inhibited acetic acid-induced capillary permeability and xylene-induced mouse ear edema in vivo. In vitro, isogarcinol decreased iNOS mRNA activity and NO content in LPS stimulated macrophagocytes by inhibiting NF-κB expression. Furthermore, isogarcinol decreased the activity of NFAT and inhibited IL-2 expression. The mechanism of action of isogarcinol is associated with down-regulation of both autoimmune and inflammatory reactions.
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Polyprenylated polycyclic acylphloroglucinols (PPAP) are a constantly growing class of natural products that exhibit a common bicyclo[3.3.1]nonatrione core and consist of currently more than 200 members. A subclassification among the various natural products of this class includes the position of the exocyclic acyl group, the prenylation grade of the core, and the relative configuration at C-7 within the core. About 10% of the reported structures, however, possess an additional chiral center at C-6. Herein we describe a straightforward access to guttiferone A and epi-guttiferone A, in which full control of stereoselectivity is achieved via conformational control, and a strict separation of framework decorating from framework constructing operations sets the stage for a short 13-step synthesis.
Article
Garcinol, a polyisoprenylated benzophenone, from Garcinia indica fruit rind has possessed anti-inflammatory, antioxidant, anti-proliferation and anticancer activities. However, the anticancer mechanisms of garcinol in lung cancer were still unclear. Therefore, we examine the effects of garcinol on anti-proliferation in human lung cancer cells. Treatments with garcinol for 24 h exhibited morphological changes and inhibited the proliferation of H460 (p53-wild type) and H1299 (p53-null) cells in a dose- and time-dependent manners. Furthermore, a significant G1 cell cycle arrest was observed in a dose-dependent treatment after H1299 cells were exposed in garcinol whereas garcinol induced apoptosis rather than cell cycle arrest in H460 cells. Moreover, cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), cyclin D1 and cyclin D3 were decreased although cyclin E and cyclin-dependent kinase 6 (CDK6) were increased in garcinol-treated H1299 cells. Meanwhile, the protein levels of CDK inhibitors p21Waf1/Cip1 and p27KIP1 also exhibited to be up-regulated after garcinol treatments. The enhanced protein-associated level between p21Waf1/Cip1 and CDK4/2 rather than p27KIP1 and CDK4/2 was demonstrated in garcinol-treated cells. Additionally, knock-down p21Waf1/Cip1 by specific siRNA competently prevented garcinol-induced G1 arrest. Besides, garcinol also inhibited ERK and p38-MAPK activations in time-dependent mode. The pre-treatment with p38-MAPK inhibitor but not ERK inhibitor raised garcinol-induced G1 population cells. Co-treatment with p38-MAPK inhibitor and garcinol synergistically elevated cyclin E, p21Waf1/Cip1 and p27Kip1 expressions. Meanwhile, overexpression dominant negative p38-MAPK also enhanced garcinol-induced p21Waf1/Cip1 expression in H1299 cells. Accordingly, our data suggested that garcinol induced G1 cell cycle arrest and apoptosis in lung cancer cells under different p53 status. The p53-independent G1 cell cycle arrest induced by garcinol might be through up-regulation of p21Waf1/Cip1 triggered from p38-MAPK signaling inactivation.
Article
Garcinol (1), a polyisoprenylated benzophenone occurring in Garcinia species, has been reported to exert anti-inflammatory activity in LPS-stimulated macrophages, through inhibition of NF-κB and/or JAK/STAT-1 activation. In order to provide deeper insight into its effects on the cytokine signaling pathway and to clarify the underlying molecular mechanisms, 1 was isolated from the fruits of Garcinia cambogia along with two other polyisoprenylated benzophenones, guttiferones K (2) and guttiferone M (3), differing from each other in their isoprenyl moieties and their positions on the benzophenone core. The affinities of 1-3 for the STAT-1 protein have been evaluated by surface plasmon resonance and molecular docking studies and resulted in KD values in the micromolar range. Consistent with the observed high affinity toward the STAT-1 protein, garcinol and guttiferones K and M were able to modulate cytokine signaling in different cultured cell lines, mainly by inhibiting STAT-1 nuclear transfer and DNA binding, as assessed by an electrophorectic mobility shift assay.
Article
Two isoprenylated benzophenone derivatives, camboginol and cambogin, have been isolated from the latex of The structure of camboginol and its conversion to cambogin, an enantiomer of isoxanthochymol, has been deduced.
Article
Maclurin, 1,3,5,6- and 1,3,6,7-tetrahydroxyxanthones co-exist inSymphonia globulifera L. from Buganda. The biogenetic significance of this observation is discussed.
Article
Enolether cyclischer Ketone 1 reagieren mit Malonyldichlorid (2) in Ether unter zweifacher Acylierung zu [n](2.4)Phloroglucinophanen bzw. deren Tautomeren oder Derivaten (Acetale, Ether); nach nichtwäßriger Aufarbeitung resultieren die Bicyclen 5, 6, nach wäßriger Aufarbeitung die Bicyclen 7–10. Die unterschiedliche Produktbildung läßt sich mit den Kenntnissen der Struktur- und Bindungsverhältnisse in ungesättigten bicyclischen Systemen bzw. Metacyclophanen plausibel deuten. Aus der nachgewiesenen benzoiden Struktur der tautomeriefähigen Metacyclophane 9f und 10g ist zu folgern, daß auch noch [8]- bzw. [7]Metacyclophane relativ spannungsfrei sind. Mittels 18O-Markierung konnte für die Etherspaltung am Beispiel der Methylarylether 6d und 6h ein Additions-Eliminierungs-Mechanismus nachgewiesen werden. Für die Verbindungen 7b, d und 10h wurden Röntgenstrukturanalysen durchgeführt. Enol Ethers, XV1). Synthesis and Structure of [n](2.4)Phloroglucinophanes Enol ethers of cyclic ketones 1 react with malonyl dichloride (2) in ether by double acylation to yield [n](2.4)phloroglucinophanes, their tautomers or derivatives (acetales, ethers) resp.; after non aqueous workup the bicyclic compounds 5, 6, after workup in water the bicyclic compounds 7–10 resulted. The different product formation can be explained by the known relations of structure and binding for unsaturated bicyclic systems and metacyclophanes, resp. From the benzoic structures of the metacyclophanes 9f and 10g it can be concluded, that even [8]- and [7]metacyclophanes are relatively free of strain. For the cleavage of the methyl aryl ethers 6d and 6h an addition elimination mechanism could be established with H218O. Crystal structure determinations were carried out for 7b, d and 10h.
Article
Constitutive activation of pro-inflammatory transcription factors such as signal transducers and activators of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) plays a pivotal role in the proliferation and survival of head and neck squamous cell carcinoma (HNSCC). Thus, agents which can modulate deregulated STAT3 and NF-κB activation have a great potential both for the prevention and treatment of HNSCC. In the present report, we investigated the potential effects of garcinol, an active component of Garcinia indica on various inflammatory mediators involved in HNSCC progression using cell lines and xenograft mouse model. We found that garcinol inhibited constitutively activated STAT3 in HNSCC cells in a time and dose dependent manner which correlated with the suppression of the upstream kinases (c-Src, JAK1 and JAK2) in HNSCC cells. Also, we noticed that the generation of reactive oxygen species is involved in STAT3 inhibitory effect of garcinol. Furthermore, garcinol exhibited an inhibitory effect on constitutive NF-κB activation, mediated through the suppression of TGF beta activated kinase 1 (TAK1), and IκB kinase (IKK) activation in HNSCC cells. Garcinol also down-regulated the expression of various gene products involved in cell proliferation, survival, and angiogenesis that led to the suppression of cell proliferation and induction of apoptosis in HNSCC cells. When administered i.p., garcinol inhibited the growth of human HNSCC xenograft tumors in male athymic nu/nu mice. Overall our results suggest for the first time that garcinol mediates its anti-tumor effects in HNSCC cells and mouse model through the suppression of multiple pro-inflammatory cascades.
Article
Alterations in microRNA (miRNA/miR) genes are of biological importance in the pathophysiology of cancers, including pancreatic cancer (PaCa). Although growing evidence supports the role of miRNA in cancer, their response to dietary phytochemicals is less known. Previously, we showed that garcinol induces PaCa cell growth arrest and apoptosis in vitro. The present study, discusses chemo-sensitization by garcinol in synergism with first-line PaCa drug, gemcitabine. The miRNA expression profile of gemcitabine-resistant Panc-1 cells treated with garcinol and/or gemcitabine was also evaluated. Garcinol synergizes with gemcitabine to inhibit cell proliferation and induce apoptosis in PaCa cells with significant modulation of key cancer regulators including PARP, VEGF, MMPs, ILs, caspases, and NF-κB. In addition, biostatistical analyses, quantitative reverse transcription PCR data, and in silico modeling using TargetScan5, PicTar, and DNA intelligent analysis, microT-V.B4 database showed that these two agents modulated a number of microRNAs (miR-21, miR-196a, miR-495, miR-605, miR-638, and miR-453) linked to various canonical oncogenic signaling pathways. We identified garcinol-specific miRNA biomarkers that sensitize PaCa cells to gemcitabine treatment, thus attenuating the drug-resistance phenotype. These results prompt further interest in garcinol and gemcitabine combination strategy as a drug modality to improve treatment outcome in patients diagnosed with PaCa.
Article
Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis and can be targeted for cancer prevention. To develop potent topical agents for oral cancer chemoprevention, 5 known 5-Lox inhibitors from dietary and synthetic sources (Zileuton, ABT-761, licofelone, curcumin, and garcinol) were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis.
Article
Garcinol, a polyisoprenylated benzophenone, was purified from Garcinia indica fruit rind. The effects of garcinol and curcumin on cell viability in human leukemia HL-60 cells were investigated. Garcinol and curcumin displayed strong growth inhibitory effects against human leukemia HL-60 cells, with estimated IC50 values of 9.42 and 19.5 μM, respectively. Garcinol was able to induce apoptosis in a concentration- and time-dependent manner; however, curcumin was less effective. Treatment with garcinol caused induction of caspase-3/CPP32 activity in a dose- and time-dependent manner, but not caspase-1 activity, and induced the degradation of poly(ADP-ribose) polymerase (PARP). Pretreatment with caspase-3 inhibitor inhibited garcinol-induced DNA fragmentation. Treatment with garcinol (20 μM) caused a rapid loss of mitochondrial transmembrane potential, release of mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 processing. The cleavage of D4-GDI, an abundant hematopoietic cell GDP dissociation inhibitor for the Ras-related Rho family GTPases, occurred simultaneously with the activation of caspase-3 but preceded DNA fragmentation and the morphological changes associated with apoptotic cell death. Of these, Bcl-2, Bad, and Bax were studied. The level of expression of Bcl-2 slightly decreased, while the levels of Bad and Bax were dramatically increased in cells treated with garcinol. These results indicate that garcinol allows caspase-activated deoxyribonuclease to enter the nucleus and degrade chromosomal DNA and induces DFF-45 (DNA fragmentation factor) degradation. It is suggested that garcinol-induced apoptosis is triggered by the release of cytochrome c into the cytosol, procaspase-9 processing, activation of caspase-3 and caspase-2, degradation of PARP, and DNA fragmentation caused by the caspase-activated deoxyribonuclease through the digestion of DFF-45. The induction of apoptosis by garcinol may provide a pivotal mechanism for its cancer chemopreventive action. Keywords: Garcinol; curcumin; apoptosis; cytochrome c; caspase-9; caspase-2; caspase-3; poly(ADP-ribose) polymerase; DNA fragmentation factor; caspase-activated deoxyribonuclease
Article
Antioxidant actions of garcinol (1), a polyisoprenylated benzophenone, purified from Garcinia indica fruit rind, are believed to contribute to its chemopreventive activity. However, the mechanisms of its antioxidant reactions remain unclear. The objective of this study was to characterize the reaction products of garcinol with peroxyl radicals generated by thermolysis of the azo initiator azo-bis-isobutyrylnitrile (AIBN). Structure elucidation of these products can provide insights into specific mechanisms of antioxidant reactions. Four reaction products (2–5) were isolated and identified. Their structures were determined on the basis of detailed high field 1D and 2D spectral analysis. The identification of these products provides the first unambiguous proof that the double bond of the isopentenyl group is a principal site of the antioxidant reaction of 1. The induction of apoptosis in human leukemia HL-60 cells, the inhibition of NO generation, and the inhibition of LPS-induced iNOS gene expression by Western blot analysis by 1 and its four oxidation products (2–5) were investigated.
Article
Unkonventionelles Vorgehen: Die direkten Totalsynthesen von Nemoroson (1) and Clusianon (2) gelangen durch die Erzeugung und Umwandlung ungewöhnlicher Anionen ausgehend von der gemeinsamen Zwischenstufe 3 (siehe Schema). Als Schlüsselschritte beim Gerüstaufbau wurden eine allylierende Desaromatisierung und eine iodierende Cyclisierung genutzt. Die Acylphloroglucin-Naturstoffe zeigen vielversprechende Zytotoxizität bzw. Anti-HIV-Aktivität.
Article
Non-homologous end joining (NHEJ), a major pathway used to repair DNA double-strand breaks (DSBs) generated by ionizing radiation (IR), requires chromatin remodeling at DSB sites through the acetylation of histones by histone acetyltransferases (HATs). However, the effect of compounds with HAT inhibitory activities on the DNA damage response (DDR), including the NHEJ and cell cycle checkpoint, as well as on the radiosensitivity of cancer cells, remains largely unclear. Here, we investigated whether garcinol, a HAT inhibitor found in the rinds of Garcinia indica fruit (called mangosteens), has effects on DDR, and whether it can be used for radiosensitization. The following assays were used to examine the effect of garcinol on the inhibition of DSB repair, including the following: a conventional neutral comet assay; a cell-based assay recently developed by us, in which NHEJ repair of DSBs on chromosomal DNA was evaluated; the micrococcal nuclease sensitivity assay; and immunoblotting for autophosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We assessed the effect of garcinol on the cell cycle checkpoint after IR treatment by analyzing the phosphorylation levels of checkpoint kinases CHK1 and CHK2 and histone H3, and by cell cycle profile analysis using flow cytometry. The radiosensitizing effect of garcinol was assessed by a clonogenic survival assay, whereas its effects on apoptosis and senescence were examined by annexin V and senescence-associated β-galactosidase (SA-β-Gal) staining, respectively. We found that garcinol inhibits DSB repair, including NHEJ, without affecting cell cycle checkpoint. Garcinol radiosensitized A549 lung and HeLa cervical carcinoma cells with dose enhancement ratios (at 10% surviving fraction) of 1.6 and 1.5, respectively. Cellular senescence induced by IR was enhanced by garcinol. These results suggest that garcinol is a radiosensitizer that inhibits NHEJ and facilitates senescence without impairing activation of the cell cycle checkpoint.
Article
Polyprenylated polycyclic acylphloroglucines (PPAPs) are a family of natural products that possess a wide range of different important biological activities because of the relative position and configuration of four substituents that decorate one common central bicyclo[3.3.1]nonane-2,4,9-trione core. The rigid bicyclic framework with its lipophilic side chains and its hydrophilic trione moiety represents a nature-derived lead structure that arranges the substituents (R(1) to R(4)) into a defined topographical orientation. As the substituents are responsible for the biological activities, the seven-step synthetic approach presented here sets the stage for an iterative introduction of R(1) to R(4) and thus generates structurally diverse trans-type B PPAPs. Four natural and one non-natural trans-type B PPAPs were prepared starting from acetylacetone with overall yields that ranged from 6 to 22%. The concept of separating framework construction from decorating transformations plus the minimization of protecting-group operations are the key issues for the realization of our synthetic approach.
Article
Garcinol, derived from Garcinia indica and other related species, has been found to modulate several cell signalling pathways involved in apoptosis and cancer development. Growth arrest and DNA damage-inducible gene 153 (GADD153) is a member of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors; it is expressed at low levels under normal conditions but strongly induced upon growth arrest, DNA damage, and endoplasmic reticulum (ER) stress. This study investigated the effect of garcinol on Hep3B cells, a human hepatocellular cancer cell line lacking functional p53, with the goal of elucidating the molecular mechanisms of p53-independent apoptosis in hepatocellular cancer. Overall, garcinol activated not only the death receptor and the mitochondrial apoptosis pathways but also the ER stress modulator GADD153. Garcinol treatment led to the accumulation of reactive oxygen species (ROS), increased GADD153 expression, and reduced mitochondrial membrane potential. An increase in the Bax/Bcl-2 ratio resulted in enhanced apoptosis. Caspase-8 and tBid (truncated Bid) expression also increased in a time-dependent manner. The enzymatic activities of caspase-3 and caspase-9 increased approximately 13-fold and 7.8-fold, respectively. In addition, the proteolytic cleavage of poly-(ADP-ribose)-polymerase (PARP) and DNA fragmentation factor-45 (DFF-45) increased in dose- and time-dependent manners. Our data suggest a promising therapeutic application of garcinol in p53-independent apoptosis in cancers.
Article
Histone acetyltransferases (HATs) are a class of epigenetic enzymes crucial for chromatin restructuring and transcriptional regulation in eukaryotic cells, thus being a promising target for therapeutic development. Nonetheless, differently from histone deacetylases (HDACs) inhibitors, there is still paucity of small-molecule modulators of HAT activity. After a decline during past decade, natural products and their derivatives could be once again a valuable tool in the lead discovery process and meet such need of Novel Chemical Entities (NCEs). In this review, we will provide a comprehensive summary on the discovery of small-molecule HAT modulators from naturally occurring molecular scaffolds.
Article
Previous studies have demonstrated that the persistent exposure of human bronchial epithelial cells to nicotine (Nic) through nicotinic acetylcholine receptors increases cyclin D1 promoter activity and protein expression. The main purpose of this study is to elucidate the carcinogenic role of cyclin D3, which is involved in breast tumorigenesis when induced by Nic. Real-time PCR analysis revealed that cyclin D3 is highly expressed at the mRNA level in surgically dissected breast tumor tissue, compared to the surrounding normal tissue (tumor/normal fold ratio = 17.93, n = 74). To test whether Nic/nicotinic acetylcholine receptor (nAChR) binding could affect cyclin D3 expression in human breast cancer cells, the transformed cell line MCF-10A-Nic (DOX) was generated from normal breast epithelial cells (MCF-10A) with inducible α9-nAChR gene expression, using the adenovirus tetracycline-regulated Tet-off system. Tet-regulated overexpression of α9-nAChR in MCF-10A-Nic (DOX) xenografted BALB/c-nu/nu mice resulted in a significant induction of cyclin D3. In contrast, cyclin D3 expression was down-regulated in α9-nAChR knock-down (siRNA) MDA-MB-231-xenografted tumors in NOD.CB17-PRKDC(SCID)/J(NOD-SCID) mice. Furthermore, we found that Nic-induced human breast cancer (MDA-MB-231) cell proliferation was inhibited by 1 μM of garcinol (Gar), isolated from the edible fruit Garcinia indica, through down-regulation of α9-nAChR and cyclin D3 expression. These results suggest that α9-nAChR-mediated cyclin D3 overexpression is important for nicotine-induced transformation of normal human breast epithelial cells. The homeostatic regulation of cyclin D3 has the potential to be a molecular target for antitumor chemotherapeutic or chemopreventive purposes in clinical breast cancer patients.
Article
Garcinol, obtained from Garcinia indica in tropical regions, is used for its numerous biological effects. Its anti-cancer activity has been suggested but the mechanism of action has not been studied in-detail, especially there is no report on its action against breast cancer cells. Here we tested our hypothesis that garcinol may act as an anti-proliferative and apoptosis-inducing agent against breast cancer cell lines. Using multiple techniques such as MTT, Histone-DNA ELISA, Annexin V-PI staining, Western blot for activated caspases and cleaved PARP, homogenous caspase-3/7 fluorometric assay and EMSA, we investigated the mechanism of apoptosis-inducing effect of garcinol in ER-positive MCF-7 and ER-negative MDA-MB-231 cells. We found that garcinol exhibits dose-dependent cancer cell-specific growth inhibition in both the cell lines with a concomitant induction of apoptosis, and has no effect on non-tumorigenic MCF-10A cells. Our results suggested induction of caspase-mediated apoptosis in highly metastatic MDA-MB-231 cells by garcinol. Down-regulation of NF-kappaB signaling pathway was observed to be the mechanism of apoptosis-induction. Garcinol inhibited constitutive NF-kappaB activity, which was consistent with down-regulation of NF-kappaB-regulated genes. This is the first report on anti-proliferative and apoptosis-inducing action of garcinol against human breast cancer cells and the results suggest that this natural compound merits investigation as a potential chemo-preventive/-therapeutic agent, especially against breast cancer.
Article
Transcriptional factors of the NF-kappaB family and STAT3 are ubiquitously expressed and control numerous physiological processes including development, differentiation, immunity, metabolism and cancer. Both NF-kappaB and STAT3 are rapidly activated in response to various stimuli including stresses and cytokines, although they are regulated by entirely different signaling mechanisms. Once activated, NF-kappaB and STAT3 control the expression of anti-apoptotic, pro-proliferative and immune response genes. Some of these genes overlap and require transcriptional cooperation between the two factors. The activation of and interaction between STAT3 and NF-kappaB plays a key role in controlling the dialog between the malignant cell and its microenvironment, especially with inflammatory/immune cells that infiltrate tumors. Quite often, cytokines whose expression is induced in response to NF-kappaB in immune cells of the tumor microenvironment lead to STAT3 activation in both malignant and immune cells. While within malignant and pre-malignant cells STAT3 exerts important oncogenic functions, within inflammatory cells it may also suppress tumor promotion through its anti-inflammatory effects. Other interactions and forms of crosstalk between NF-kappaB and STAT3 include physical interaction between the two, cooperation of these factors at gene promoters/enhancers, the NF-kappaB dependent expression of inhibitors of STAT3 activation and the participation of STAT3 in inflammatory cells in the negative regulation NF-kappaB. Despite these versatile and occasionally antagonistic interactions, NF-kappaB and STAT3 cooperate to promote the development and progression of colon, gastric and liver cancers. In addition to explaining the molecular pathogenesis of cancer, these interactions also offer opportunities for the design of new therapeutic interventions.
Article
Garcinol (camboginol) from the fruit rind of Guttiferae species shows anti-carcinogenic and anti-inflammatory properties, but the underlying molecular mechanisms are unclear. Here we show that garcinol potently interferes with 5-lipoxygenase (EC 7.13.11.34) and microsomal prostaglandin (PG)E2 synthase (mPGES)-1 (EC 5.3.99.3), enzymes that play pivotal roles in inflammation and tumorigenesis. In cell-free assays, garcinol inhibited the activity of purified 5-lipoxygenase and blocked the mPGES-1-mediated conversion of PGH2 to PGE2 with IC50 values of 0.1 and 0.3 microM, respectively. Garcinol suppressed 5-lipoxygenase product formation also in intact human neutrophils and reduced PGE2 formation in interleukin-1beta-stimulated A549 human lung carcinoma cells as well as in human whole blood stimulated by lipopolysaccharide. Moreover, garcinol interfered with isolated cyclooxygenase (COX)-1 (EC 1.14.99.1, IC50 = 12 microM) and with the formation of COX-1-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid and thromboxane B2 in human platelets. In contrast, neither Ca2+-ionophore (A23187)-induced arachidonic acid release in neutrophils nor COX-2 activity in A549 cells or whole blood, measured as formation of 6-keto PGF1alpha, or isolated human recombinant COX-2 were significantly affected by garcinol (< or = 30 microM). Together, the high potency of garcinol to selectively suppress PGE2 synthesis and 5-lipoxygenase product formation provides a molecular basis for the anti-inflammatory and anti-carcinogenic effects of garcinol and rationalizes its therapeutic use.
Article
Breast cancer remains the major cause of cancer-related deaths in women world-wide. The heterogeneity of breast cancer has further complicated the progress of target-based therapies. Triple negative breast cancers, lacking estrogen receptor, progesterone receptor and the Her-2/neu (ErbB2), represent a highly aggressive breast cancer subtype, that are difficult to treat. Pleiotropic agents, such as those found in nature, can target receptor-positive as well as receptor-negative cancer cells, suggesting that such agents could have significant impact in breast cancer prevention and/or therapy. Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone) is one such agent which has anti-tumor activity against several cancers. However, its mechanism of action against breast cancer is not clearly understood. We hypothesized that plumbagin may act as an effective agent against breast cancer especially triple negative breast cancer. We tested our hypothesis using ER-positive MCF-7 and ER-negative MDA-MB-231 (triple negative) breast cancer cells, and we found that plumbagin significantly inhibits the growth of breast cancer cells with no effect on normal breast epithelial cells. We also found that plumbagin induces apoptosis with concomitant inactivation of Bcl-2 and the DNA binding activity of NF-kappaB. Bcl-2 over-expression resulted in attenuation of plumbagin-induced effects, suggesting that the inhibition of cell growth and induction of apoptosis by plumbagin is in part due to inactivation of NF-kappaB/Bcl-2 pathway. To our knowledge, this is the first report, showing mechanistic and cancer cell specific apoptosis-inducing effects of plumbagin in breast cancer cells, suggesting the potential role of plumbagin in the prevention and/or treatment of breast cancer.
Article
The modifying effects of dietary feeding of a polyisoprenylated benzophenone, garcinol, isolated from Garcinia indica fruit rind on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. We also assessed the effects of garcinol on proliferating cell nuclear antigen (PCNA) index in ACF and activities of detoxifying enzymes of glutathione S-transferase (GST) and quinone reductase (QR) in liver. In addition, we examined the effects of garcinol on 12-O-tetradecanoylphorbol-13-acetate-induced O2– generation in differentiated human promyelocytic HL-60 cells and lipopolysaccharide (LPS)- and interferon (IFN)-γ-induced nitric oxide (NO) generation in mouse macrophage RAW 264.7 cells. Western blotting analysis of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression was done in LPS- and IFN-γ-treated mouse macrophage RAW 264.7 cells. Rats were given subcutaneous injections of AOM (15 mg/kg body wt) once a week for 3 weeks to induce ACF. They also received the experimental diet containing 0.01 or 0.05% garcinol for 5 weeks, starting 1 week before the first dosing of AOM. AOM exposure produced 97 ± 15 ACF/rat at the end of the study (week 5). Dietary administration of garcinol caused significant reduction in the frequency of ACF: 72 ± 15 (26% reduction, P < 0.01) at a dose of 0.01% and 58 ± 8 (40% reduction, P < 0.001) at a dose of 0.05%. Garcinol administration significantly lowered PCNA index in ACF. Feeding of garcinol significantly elevated liver GST and QR activities. In addition, garcinol could suppress O2– and NO generation and expression of iNOS and COX-2 proteins. These findings might suggest possible chemopreventive ability of garcinol, through induction of liver GST and QR, inhibition of O2– and NO generation and/or suppression of iNOS and COX-2 expression, on colon tumorigenesis.
Article
The state of chromatin (the packaging of DNA in eukaryotes) has long been recognized to have major effects on levels of gene expression, and numerous chromatin-altering strategies-including ATP-dependent remodeling and histone modification-are employed in the cell to bring about transcriptional regulation. Of these, histone acetylation is one of the best characterized, as recent years have seen the identification and further study of many histone acetyltransferase (HAT) proteins and their associated complexes. Interestingly, most of these proteins were previously shown to have coactivator or other transcription-related functions. Confirmed and putative HAT proteins have been identified from various organisms from yeast to humans, and they include Gcn5-related N-acetyltransferase (GNAT) superfamily members Gcn5, PCAF, Elp3, Hpa2, and Hat1: MYST proteins Sas2, Sas3, Esa1, MOF, Tip60, MOZ, MORF, and HBO1; global coactivators p300 and CREB-binding protein; nuclear receptor coactivators SRC-1, ACTR, and TIF2; TATA-binding protein-associated factor TAF(II)250 and its homologs; and subunits of RNA polymerase III general factor TFIIIC. The acetylation and transcriptional functions of these HATs and the native complexes containing them (such as yeast SAGA, NuA4, and possibly analogous human complexes) are discussed. In addition, some of these HATs are also known to modify certain nonhistone transcription-related proteins, including high-mobility-group chromatin proteins, activators such as p53, coactivators, and general factors. Thus, we also detail these known factor acetyltransferase (FAT) substrates and the demonstrated or potential roles of their acetylation in transcriptional processes.
Article
Garcinol, a polyisoprenylated benzophenone derivative, was purified from Garcinia indica fruit rind, and its free radical scavenging activity was studied using electron spin resonance (ESR) spectrometry. In the hypoxanthine/xanthine oxidase system, emulsified garcinol suppressed superoxide anion to almost the same extent as DL-alpha-tocopherol by weight. In the Fenton reaction system, garcinol also suppressed hydroxyl radical more strongly than DL-alpha-tocopherol. In the H(2)O(2)/NaOH/DMSO system, garcinol suppressed superoxide anion, hydroxyl radical, and methyl radical. It was thus confirmed that this derivative is a potent free radical scavenger and able to scavenge both hydrophilic and hydrophobic ones including reactive oxygen species. Orally administered garcinol prevented acute ulceration in rats induced by indomethacin and water immersion stress caused by radical formation. These results suggested garcinol might have potential as a free radical scavenger and clinical application as an antiulcer drug.
Article
Microtubule disassembly inhibitory properties have been established for the known polyisoprenylated benzophenones xanthochymol (1a) and guttiferone E (1b). The compounds were isolated from the fruits of Garcinia pyrifera collected in Malaysia. A structure-activity relationship study, including natural and semisynthetic derivatives, delineated some structural features necessary for the interaction with tubulin within this compound class.
Article
Transcriptional regulation in eukaryotes occurs within a chromatin setting and is strongly influenced by nucleosomal barriers imposed by histone proteins. Among the well-known covalent modifications of histones, the reversible acetylation of internal lysine residues in histone amino-terminal domains has long been positively linked to transcriptional activation. Recent biochemical and genetic studies have identified several large, multisubunit enzyme complexes responsible for bringing about the targeted acetylation of histones and other factors. This review discusses our current understanding of histone acetyltransferases (HATs) or acetyltransferases (ATs): their discovery, substrate specificity, catalytic mechanism, regulation, and functional links to transcription, as well as to other chromatin-modifying activities. Recent studies underscore unexpected connections to both cellular regulatory processes underlying normal development and differentiation, as well as abnormal processes that lead to oncogenesis. Although the functions of HATs and the mechanisms by which they are regulated are only beginning to be understood, these fundamental processes are likely to have far-reaching implications for human biology and disease.