Cardamonin

IC50: 1.2 μM (NF-κB activation) [1]

Cardamonin (2′,4′-dihydroxy-6′-methoxychalcone), a chalcone isolated from the fruits of Alpinia rafflesiana, shows anti-inflammatory activity by targeting the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. NF-κB is a protein complex that controls cytokine production, transcription of DNA and cell survival.

In vitro: Cardamonin is a potential anti-inflammatory drug that targets the NF-κB pathway, which leads to suppress both NO and PGE2 synthesis, iNOS and COX-2 expression and enzymatic activity. The inhibition activation was due to a dose-dependent inhibition of phosphorylation and degradation of I-κBα, which resulted in a reduction of p65 NF-κB nuclear translocation [2]. Cardamonin also appears to inhibit prostaglandin E2, thromboxane B2 production, tumor necrosis factor a (TNF-a) release, and intracellular reactive oxygen species generation, all in a dose-dependent manner [3]

In vivo: Cardamonin shows protective effects on acute lung injury in sepsis. In mice, the results showed that cardamonin decreases systemic inflammatory responses, during sepsis, by downregulating TNF-a and interleukins [3].

Clinical trial: So far, no clinical study has been conducted.

References:
[1] Lee JH, Jung HS, Giang PM, Jin X, Lee S, Son PT, Lee D, Hong YS, Lee K, Lee JJ.  Blockade of nuclear factor-kappaB signaling pathway and anti-inflammatory activity of cardamomin, a chalcone analog from Alpinia conchigera. J Pharmacol Exp Ther. 2006 Jan;316(1):271-8. Epub 2005 Sep 23.
[2] Israf DA, Khaizurin TA, Syahida A, Lajis NH, Khozirah S.  Cardamonin inhibits COX and iNOS expression via inhibition of p65NF-kappaB nuclear translocation and Ikappa-B phosphorylation in RAW 264.7 macrophage cells. Mol Immunol. 2007 Feb;44(5):673-9. Epub 2006 Jun 13.
[3] Gonalves LM, Valente IM, Rodrigues JA.  An overview on cardamonin. J Med Food. 2014 Jun;17(6):633-40.

Antiproliferative activity and induction of apoptosis in PC-3 cells by the chalcone cardamonin from Campomanesia adamantium (Myrtaceae) in a bioactivity-guided study.[Pubmed:24514747]

Molecules. 2014 Feb 7;19(2):1843-55.

The Myrtaceae family is a common source of medicines used in the treatment of numerous diseases in South America. In Brazil, fruits of the Campomanesia species are widely used to make liqueurs, juices and sweets, whereas leaves are traditionally employed as a medicine for dysentery, stomach problems, diarrhea, cystitis and urethritis. Ethanol extracts of Campomanesia adamantium (Myrtaceae) leaves and fruits were evaluated against prostate cancer cells (PC-3). The compound (2E)-1-(2,4-dihydroxy-6-methoxyphenyl)-3-phenylprop-2-en-1-one, Cardamonin) was isolated from ethanol extracts of C. adamantium leaves in a bioactivity-guided study and quantified by UPLC-MS/MS. In vitro studies showed that the isolated chalcone Cardamonin inhibited prostate cancer cell proliferation and decreased the expression of NFkB1. Moreover, analysis by flow cytometry showed that this compound induced DNA fragmentation, suggesting an effect on apoptosis induction in the PC-3 cell line.

Novel suppressive effects of cardamonin on the activity and expression of transglutaminase-2 lead to blocking the migration and invasion of cancer cells.[Pubmed:23201552]

Life Sci. 2013 Feb 7;92(2):154-60.

AIMS: Alpinia katsumadai was recently found in our previous study to have anti-migratory and anti-invasion activities against HT-1080 cells. However, the study did not demonstrate the exact component of Alpinia katsumadai with anti-migratory and anti-invasive activities. We tested the effects and relevant mechanism of Cardamonin (CDN) on the migration and invasion of cancer cells. MAIN METHODS: Migration and invasion of cancer cells were measured using multi-well chambers. Zymography and Western blots were used to examine the effects of CDN on the activities of matrix metalloproteinases (MMPs) and expression of transglutaminase-2 (Tgase-2). KEY FINDINGS: CDN, but not alpinetin, dose-dependently suppressed the migration and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced invasion of HT-1080 sarcoma cells. CDN suppressed the expression of Tgase-2, MMP-2, NF-kappaB and MMP-9 in HT-1080 cells, and suppressed MMP-2 and MMP-9 activities. Gene silencing of Tgase-2 suppressed the migration and invasion of HT-1080 cells and suppressed the activities of MMP-2 and MMP-9. Migration of various cancer cells having high levels of Tgase-2 were also inhibited by CDN. CDN and Alpinia katsumadai extracts also directly inhibited the activity of Tgase-2. SIGNIFICANCE: CDN inhibits migration of several cancer cell lines expressing Tgase-2 via suppression of Tgase-2 expression and inhibition of Tgase-2 activity. The finding that CDN has Tgase-2 inhibitory activity will give us a new scaffold or clue of pharmacophore for the development of more effective Tgase-2 inhibitors.

Vasorelaxant effects of cardamonin and alpinetin from Alpinia henryi K. Schum.[Pubmed:11336110]

J Cardiovasc Pharmacol. 2001 May;37(5):596-606.

The vascular effects of Cardamonin and alpinetin from Alpinia henryi K. Schum. were examined in the rat isolated mesenteric arteries. 1H and 13C nuclear magnetic resonance spectra showed that Cardamonin is present in trans-form, and single-crystal radiographic structure revealed that alpinetin is present in S configuration. Both Cardamonin and alpinetin produced a rightward shift in the concentration-response curve for phenylephrine in a noncompetitive manner, and they induced relaxation of phenylephrine-preconstricted arteries with respective mean inhibitory concentrations (IC50) of 9.3+/-0.6 microM and 27.5+/-2.8 microM. Both compounds also relaxed arteries preconstricted by endothelin I or U46619. Their relaxant effects were decreased in endothelium-removed rings. Pretreatment with N(G)-nitro-L-arginine methyl ester or methylene blue inhibited relaxation induced by both agents, and pretreatment with L-arginine reversed the effect of N(G)-nitro-L-arginine methyl ester on Cardamonin-induced endothelium-dependent relaxation. The relaxant effects of Cardamonin and alpinetin were unaffected by indomethacin (3 microM). Cardamonin and alpinetin inhibited 60 mM K+-induced contraction with respective IC50 of 11.5+/-0.3 microM and 37.9+/-3.6 microM. In addition, both agents inhibited the transient contraction induced by 3 microM phenylephrine or by 10 mM caffeine in Ca2+-free Krebs solution. Finally, these two agents also concentration dependently relax the arteries preconstricted by 1 microM phorbol 12,13-diacetate in Ca2+-free Krebs solution. These results indicate that purified Cardamonin and alpinetin from A. henryi K. Schum. relaxed rat mesenteric arteries through multiple mechanisms. They induced both endothelium-dependent and -independent relaxation; the former is likely mediated by nitric oxide whereas the latter is probably mediated through nonselective inhibition of Ca2+ influx and intracellular Ca2+ release and inhibition of the protein kinase C-dependent contractile mechanism.

The effects of cardamonin on lipopolysaccharide-induced inflammatory protein production and MAP kinase and NFkappaB signalling pathways in monocytes/macrophages.[Pubmed:16894344]

Br J Pharmacol. 2006 Sep;149(2):188-98.

BACKGROUND AND PURPOSE: In this study we examined the effect of the natural product Cardamonin, upon lipopolysaccharide (LPS)-induced inflammatory gene expression in order to attempt to pinpoint the mechanism of action. EXPERIMENTAL APPROACHES: Cardamonin was isolated from the Greek plant A. absinthium L. Its effects were assessed on LPS-induced nitrite release and iNOS and COX-2 protein expression in two macrophage cell lines. Western blotting was used to investigate its effects on phosphorylation of the mitogen activated protein (MAP) kinases, ERK, JNK and p38 MAP kinase, and activation of the NFkappaB pathway, at the level of IkappaBalpha degradation and phosphorylation of NFkappaB. Also its effects on NFkappaB and GAS/GAF-DNA binding were assessed by EMSA. KEY RESULTS: Cardamonin concentration-dependently inhibited both NO release and iNOS expression but had no effect on COX-2 expression. It did not affect phosphorylation of the MAP kinases, degradation of IkappaBalpha or phosphorylation of NFkappaB. However, it inhibited NFkappaB DNA-binding in both LPS-stimulated cells and nuclear extracts of the cells (in vitro). It also inhibited IFNgamma-stimulated iNOS induction and GAS/GAF-DNA binding. CONCLUSIONS AND IMPLICATIONS: These results show that the inhibitory effect of Cardamonin on LPS-induced iNOS induction is not mediated via effects on the initial activation of the NFkappaB or MAP kinase pathways but is due to a direct effect on transcription factor binding to DNA. However, although some selectivity in Cardamonin's action is implicated by its inability to affect COX-2 expression, its exact mechanism(s) of action has yet to be identified.

Cardamonin sensitizes tumour cells to TRAIL through ROS- and CHOP-mediated up-regulation of death receptors and down-regulation of survival proteins.[Pubmed:21797841]

Br J Pharmacol. 2012 Feb;165(3):741-53.

BACKGROUND AND PURPOSE: TNF-related apoptosis-inducing ligand (TRAIL) is currently in clinical trials as a treatment for cancer, but development of resistance is a major drawback. Thus agents that can overcome resistance to TRAIL are urgently needed. Cardamonin (2',4'-dihydroxy-6'-methoxychalcone) has been shown to affect cell growth by modulating various cell signalling pathways. Hence, we investigated the effect of Cardamonin on the actions of TRAIL. EXPERIMENTAL APPROACH: The effect of Cardamonin on TRAIL was measured by plasma membrane integrity, phosphatidylserine exposure, mitochondrial activity, and activation of caspase-8, caspase-9, and caspase-3 in human colon cancer cells. KEY RESULTS: Cardamonin potentiated TRAIL-induced apoptosis and this correlated with up-regulation of both the TRAIL death receptor (DR) 4, 5 at mRNA and protein levels. TRAIL-decoy receptor DcR1 was down-regulated by Cardamonin. Induction of DRs by Cardamonin occurred in a variety of cell types. Gene silencing of the DRs by small interfering RNA (siRNA) abolished the effect of Cardamonin on TRAIL-induced apoptosis, suggesting that sensitization was mediated through the DR. Induction of the DR by Cardamonin was p53-independent but required CCAAT/enhancer binding protein homologous protein (CHOP); Cardamonin induced CHOP, and its silencing by siRNA eliminated the induction of DR5. Cardamonin increased the production of reactive oxygen species (ROS) and quenching ROS abolished its induction of receptors and enhancement of TRAIL-induced apoptosis. Cardamonin also decreased the expression of various cell survival proteins. CONCLUSIONS AND IMPLICATIONS: Cardamonin potentiates TRAIL-induced apoptosis through ROS-CHOP-mediated up-regulation of DRs, decreased expression of decoy receptor and cell survival proteins. Thus, Cardamonin has the potential to make TRAIL more effective as an anticancer therapy.

WITHDRAWN: Cardamonin Inhibits Osteoclastogenesis Induced by Tumor Cells Through Interruption of the Signaling Pathway Activated by Receptor Activator of NF-kappaB Ligand.[Pubmed:22182452]

Cancer Lett. 2011 Dec 17. pii: S0304-3835(11)00758-0.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Cardamonin Suppresses TGF-beta1-Induced Epithelial Mesenchymal Transition via Restoring Protein Phosphatase 2A Expression.[Pubmed:25767682]

Biomol Ther (Seoul). 2015 Mar;23(2):141-8.

Epithelial mesenchymal transition (EMT) is the first step in metastasis and implicated in the phenotype of cancer stem cells. Therefore, understanding and controlling EMT, are essential to the prevention and cure of metastasis. In the present study, we examined, by Western blot, reverse transcription polymerase chain reaction (RT-PCR), and confocal microscopy, the effects of Cardamonin (CDN) on transforming growth factor-beta1 (TGF-beta1)-induced EMT of A549 lung adenocarcinoma cell lines. TGF-beta1 induced expression of N-cadherin and decreased expression of E-cadherin. CDN suppressed N-cadherin expression and restored E-cadherin expression. Further, TGF-beta1 induced migration and invasion of A549 cancer cells, which was suppressed by CDN. TGF-beta1 induced c-Jun N-terminal kinase (JNK) activation during EMT, but CDN blocked it. Protein serine/threonine phosphatase 2A (PP2A) expression in A549 cancer cells was reduced by TGF-beta1 but CDN restored it. The overall data suggested that CDN suppresses TGF-beta1-induced EMT via PP2A restoration, making it a potential new drug candidate that controls metastasis.

Cardamonin inhibits COX and iNOS expression via inhibition of p65NF-kappaB nuclear translocation and Ikappa-B phosphorylation in RAW 264.7 macrophage cells.[Pubmed:16777230]

Mol Immunol. 2007 Feb;44(5):673-9.

Cardamonin, a chalcone isolated from the fruits of a local plant Alpinia rafflesiana, has demonstrated anti-inflammatory activity in cellular models of inflammation. In this report, we evaluated the ability of Cardamonin to suppress both NO and PGE2 synthesis, iNOS and COX-2 expression and enzymatic activity, and key molecules in the NF-kappaB pathway in order to determine its molecular target. Cardamonin suppressed the production of NO and PGE2 in interferon-gamma (IFN-gamma)- and lipopolysaccharide (LPS)-induced RAW 264.7 cells. This inhibition was demonstrated to be caused by a dose-dependent down-regulation of both inducible enzymes, iNOS and COX-2, without direct effect upon iNOS or COX-2 enzyme activity. Subsequently we determined that the inhibition of inducible enzyme expression was due to a dose-dependent inhibition of phosphorylation and degradation of I-kappaBalpha, which resulted in a reduction of p65NF-kappaB nuclear translocation. We conclude that Cardamonin is a potential anti-inflammatory drug lead that targets the NF-kappaB pathway.

Cardamonin ameliorates insulin resistance induced by high insulin and high glucose through the mTOR and signal pathway.[Pubmed:23512499]

Planta Med. 2013 Apr;79(6):452-8.

The mammalian target of rapamycin is crucial in the regulation of cell growth and metabolism. Recent studies suggest that the mammalian target of rapamycin and its downstream 70-kDa ribosomal S6 kinase 1 negatively modulate the insulin-signaling pathway, which is considered the main cause of insulin resistance. The aim of this study is to investigate the effects of Cardamonin, a potential inhibitor of the mammalian target of the rapamycin, on insulin-resistant vascular smooth muscle cells and the molecular mechanisms involved. Vascular smooth muscle cells were cultured with high glucose and high insulin to induce insulin resistance. The mammalian target of rapamycin was overstimulated in cells that were incubated with high glucose and high insulin, as reflected by the excessive activation of S6 kinase 1. Insulin-resistant vascular smooth muscle cells displayed hyperphosphorylation of insulin receptor substrate-1 at Ser residues 636/639, which decreased the activity of insulin receptor substrate-1. Also, the activation of protein kinase B and phosphorylation of glycogen synthesis kinase-3beta were inhibited. Cardamonin increased the 2-deoxyglucose uptake and glycogen concentration, which was reduced by insulin resistance. As with rapamycin, Cardamonin inhibited the activity of the mammalian target of rapamycin and S6 kinase 1, decreased the Ser 636/639 phosphorylation of insulin receptor substrate-1 and increased the activation of protein kinase B. Both of them increased the Ser9 phosphorylation of glycogen synthesis kinase-3beta and decreased the expression of glycogen synthesis kinase-3beta. However, neither Cardamonin nor rapamycin increased the expression of glucose transport 4 which decreased in insulin-resistant vascular smooth muscle cells. This study suggests that Cardamonin inhibited the activity of the mammalian target of rapamycin and eliminated the negative feedback of the mammalian target of rapamycin and S6 kinase 1 on the insulin-signaling pathway.

Cardamonin suppresses melanogenesis by inhibition of Wnt/beta-catenin signaling.[Pubmed:19800318]

Biochem Biophys Res Commun. 2009 Dec 18;390(3):500-5.

Wnt/beta-catenin signaling plays important roles in many developmental processes, including neural crest-derived melanocyte development. Here we show that Cardamonin, a calchone from Aplinia katsumadai Hayata, inhibited pigmentation in melanocytes through suppression of Wnt/beta-catenin signaling pathway. Cardamonin significantly suppressed the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase, which are melanocyte differentiation-associated markers, in human normal melanocytes, thereby decreasing intracellular melanin production. In addition, Cardamonin promoted the degradation of intracellular beta-catenin that was accumulated by Wnt3a-conditioned medium (Wnt3a CM) or bromoindirubin-3'-oxime (BIO), a glycogen synthase kinase-3beta (GSK-3beta) inhibitor, in HEK293 reporter cells and human normal melanocytes. Our findings indicate that Cardamonin may be a potential whitening agent for use in cosmetics and in the medical treatment of hyperpigmentation disorders.

Cardamonin, inhibits pro-inflammatory mediators in activated RAW 264.7 cells and whole blood.[Pubmed:16650843]

Eur J Pharmacol. 2006 May 24;538(1-3):188-94.

Some chalcones, such as hydroxychalcones have been reported previously to inhibit major pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha) and reactive oxygen species production by suppressing inducible enzyme expression via inhibition of the mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of critical transcription factors. In this report, the effects of Cardamonin (2',4'-dihydroxy-6'-methoxychalcone), a chalcone that we have previously isolated from Alpinia rafflesiana, was evaluated upon two cellular systems that are repeatedly used in the analysis of anti-inflammatory bioactive compounds namely RAW 264.7 cells and whole blood. Cardamonin inhibited NO and PGE(2) production from lipopolysaccharide- and interferon-gamma-induced RAW cells and whole blood with IC(50) values of 11.4 microM and 26.8 microM, respectively. Analysis of thromboxane B(2) (TxB(2)) secretion from whole blood either stimulated via the COX-1 or COX-2 pathway revealed that Cardamonin inhibits the generation of TxB(2) via both pathways with IC(50) values of 2.9 and 1.1 microM, respectively. Analysis of IC(50) ratios determined that Cardamonin was more COX-2 selective in its inhibition of TxB(2) with a ratio of 0.39. Cardamonin also inhibited the generation of intracellular reactive oxygen species and secretion of TNF-alpha from RAW 264.7 cells in a dose responsive manner with IC(50) values of 12.8 microM and 4.6 microM, respectively. However, Cardamonin was a moderate inhibitor of lipoxygenase activity when tested in an enzymatic assay system, in which not a single concentration tested was able to cause an inhibition of more than 50%. Our results suggest that Cardamonin acts upon major pro-inflammatory mediators in a similar fashion as described by previous work on other closely related synthetic hydroxychalcones and strengthens the conclusion of the importance of the methoxyl moiety substitution on the 4' or 6' locations of the A benzene ring.

Blockade of nuclear factor-kappaB signaling pathway and anti-inflammatory activity of cardamomin, a chalcone analog from Alpinia conchigera.[Pubmed:16183703]

J Pharmacol Exp Ther. 2006 Jan;316(1):271-8.

Nuclear factor-kappaB (NF-kappaB) and the signaling pathways that regulate its activity have become a focal point for intense drug discovery and development efforts. NF-kappaB regulates the transcription of a large number of genes, particularly those involved in immune, inflammatory, and antiapoptotic responses. In our search for NF-kappaB inhibitors from natural resources, we identified cardamomin, 2',4'-dihydroxy-6'-methoxychalcone, as an inhibitor of NF-kappaB activation from Alpinia conchigera Griff (Zingiberaceae). In present study, we demonstrated the effect of cardamomin on NF-kappaB activation in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and LPS-induced mortality. This compound significantly inhibited the induced expression of NF-kappaB reporter gene by LPS or tumor necrosis factor (TNF)-alpha in a dose-dependent manner. LPS-induced production of TNF-alpha and NO as well as expression of inducible nitric-oxide synthase and cyclooxygenase-2 was significantly suppressed by the treatment of cardamomin in RAW264.7 cells. Also, cardamomin inhibited not only LPS-induced degradation and phosphorylation of inhibitor kappaBalpha (IkappaBalpha) but also activation of inhibitor kappaB (IkappaB) kinases and nuclear translocation of NF-kappaB. Further analyses revealed that cardamomin did not directly inhibit IkappaB kinases, but it significantly suppressed LPS-induced activation of Akt. Moreover, cardamomin suppressed transcriptional activity and phosphorylation of Ser536 of RelA/p65 subunit of NF-kappaB. However, this compound did not inhibit LPS-induced activation of extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun NH(2)-terminal kinase, but significantly impaired activation of p38 mitogen-activated protein kinase. We also demonstrated that pretreatment of cardamomin rescued C57BL/6 mice from LPS-induced mortality in conjunction with decreased serum level of TNF-alpha. Together, cardamomin could be valuable candidate for the intervention of NF-kappaB-dependent pathological condition such as inflammation.