Garcinol—A Natural Histone Acetyltransferase Inhibitor and New Anti-Cancer Epigenetic Drug

Kopytko, Patrycja; Piotrowska, Katarzyna; Janisiak, Joanna; Tarnowski, Maciej

doi:10.3390/ijms22062828

Cited by 53 publications

(32 citation statements)

References 68 publications

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“…We demonstrate by ChIP that FOXC2 binds to its promoter and its binding affinity is enhanced by LPS treatment. Our data also reveal that garcinol, a HAT inhibitor, that is specific to p300 and PCAF (Balasubramanyam et al, 2004;Kim et al, 2020;Wang et al, 2020;Kopytko et al, 2021), represses LPS-stimulated histone acetylation at FOXC2 promoter, FOXC2 binding affinity and FOXC2 expression in HPMEC-Im. Our data shows that LPS-stimulated FOXC2 expression in primary HPMEC is also repressed by garcinol consistent with our data in immortalized HPMEC.…”

Section: Discussionsupporting

confidence: 60%

FOXC2 Autoregulates Its Expression in the Pulmonary Endothelium After Endotoxin Stimulation in a Histone Acetylation-Dependent Manner

Sheng

Menden

et al. 2021

Front. Cell Dev. Biol.

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The innate immune response of pulmonary endothelial cells (EC) to lipopolysaccharide (LPS) induces Forkhead box protein C2 (FOXC2) activation through Toll Like Receptor 4 (TLR4). The mechanisms by which FOXC2 expression is regulated in lung EC under LPS stimulation remain unclear. We postulated that FOXC2 regulates its own expression in sepsis, and its transcriptional autoregulation directs lymphatic EC cell-fate decision. Bioinformatic analysis identified potential FOXC2 binding sites in the FOXC2 promoter. In human lung EC, we verified using chromatin immunoprecipitation (ChIP) and luciferase assays that FOXC2 bound to its own promoter and stimulated its expression after LPS stimulation. Chemical inhibition of histone acetylation by garcinol repressed LPS-induced histone acetylation in the FOXC2 promoter region, and disrupted LPS-mediated FOXC2 binding and transcriptional activation. CRISPR/dCas9/gRNA directed against FOXC2-binding-element (FBE) suppressed LPS-stimulated FOXC2 binding and autoregulation by blocking FBEs in the FOXC2 promoter, and repressed expression of lymphatic EC markers. In a neonatal mouse model of sterile sepsis, LPS-induced FOXC2 binding to FBE and FOXC2 expression in lung EC was attenuated with garcinol treatment. These data reveal a new mechanism of LPS-induced histone acetylation-dependent FOXC2 autoregulation.

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Section: Discussionsupporting

confidence: 60%

FOXC2 Autoregulates Its Expression in the Pulmonary Endothelium After Endotoxin Stimulation in a Histone Acetylation-Dependent Manner

Sheng

Menden

et al. 2021

Front. Cell Dev. Biol.

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“…[ 28–30 ] These promising in vivo results warrant further investigation of garcinol as a potential antiviral drug candidate although in vitro assays with tumor cell lines revealed considerable cytotoxicity for it and its manifold antitumor activities are indeed well described. [ 28,30,36,37 ] Furthermore, a chemical fine‐tuning of garcinol might improve its affinity for HIV‐1 RT‐associated RNase H and related viral ribonucleases with Mg 2+ ‐dependent active sites. For instance, the exonuclease activity of coronavirus Nsp14 protein depends on Mg 2+ and can be a highly relevant target for such metal‐chelating compounds in future studies.…”

Section: Discussionmentioning

confidence: 99%

Garcinol from Garcinia indica inhibits HIV‐1 reverse transcriptase‐associated ribonuclease H

Corona

Seibt

Schaller

et al. 2021

Archiv der Pharmazie

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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.

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“…It has to be taken into account that most of the known dicarbonylic antioxidants exist mainly in the enolized form, as depicted in Scheme 2. In fact, apart from the enolized forms of curcumin, curcuminoids, and phenolic diketones shown in Scheme 1, the antioxidative power of compounds shown in Scheme 2, such as feruloylacetone (11 [16]), O-β-D-glucoside derivatives of β-diketones (12, [17]), garcinol (13 [18], also with potent anti-inflammatory [19] and anti-cancer [20] activities) or 2-aryl-1,3-indandiones (14, [21]), has already been reported.…”

Section: Introductionmentioning

confidence: 99%

Recent Developments in the Synthesis of β-Diketones

Gonzalo

Alcántara

2021

Pharmaceuticals

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Apart from being one of the most important intermediates in chemical synthesis, broadly used in the formation of C–C bonds among other processes, the β-dicarbonyl structure is present in a huge number of biologically and pharmaceutically active compounds. In fact, mainly derived from the well-known antioxidant capability associated with the corresponding enol tautomer, β-diketones are valuable compounds in the treatment of many pathological disorders, such as cardiovascular and liver diseases, hypertension, obesity, diabetes, neurological disorders, inflammation, skin diseases, fibrosis, or arthritis; therefore, the synthesis of these structures is an area of overwhelming interest for organic chemists. This paper is devoted to the advances achieved in the last ten years for the preparation of 1,3-diketones, using different chemical (Claisen, hydration of alkynones, decarboxylative coupling) or catalytic (biocatalysis, organocatalytic, metal-based catalysis) methodologies: Additionally, the preparation of branched β-dicarbonyl compounds by means of α-functionalization of non-substituted 1,3-diketones are also discussed.

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Garcinol—A Natural Histone Acetyltransferase Inhibitor and New Anti-Cancer Epigenetic Drug

Cited by 53 publications

References 68 publications

FOXC2 Autoregulates Its Expression in the Pulmonary Endothelium After Endotoxin Stimulation in a Histone Acetylation-Dependent Manner

FOXC2 Autoregulates Its Expression in the Pulmonary Endothelium After Endotoxin Stimulation in a Histone Acetylation-Dependent Manner

Garcinol from Garcinia indica inhibits HIV‐1 reverse transcriptase‐associated ribonuclease H

Recent Developments in the Synthesis of β-Diketones

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