Damnacanthal

The fruit of Morinda citrifolia Linn.

Damnacanthal inhibits IgE receptor-mediated activation of mast cells.[Pubmed:25656801]

Mol Immunol. 2015 May;65(1):86-93.

Damnacanthal, an anthraquinone obtained from the noni fruit (Morinda citrifolia L.), has been described to possess anti-cancer and anti-inflammatory properties. Since mast cells are key players in various inflammatory conditions as well as in cancer, we considered the possibility that the biological actions of Damnacanthal, at least partly, could be due to effects on mast cells. Many of the biological activities of mast cells are mediated by IgE receptor cross-linking, which results in degranulation with release of preformed granule mediators, as well as de novo synthesis and release of additional compounds. Here we show that Damnacanthal has profound inhibitory activity on mast cell activation through this pathway. The release of the granule compounds beta-hexosaminidase and tryptase release was completely abrogated by Damnacanthal at doses that were non-toxic to mast cells. In addition, Damnacanthal inhibited activation-dependent pro-inflammatory gene induction, as well as cytokine/chemokine release in response to mast cell stimulation. The mechanism underlying Damnacanthal inhibition was linked to impaired phosphorylation of Syk and Akt. Furthermore, Damnacanthal inhibited mast cell activation in response to calcium ionophore A23187. Altogether, the data presented here demonstrate that Damnacanthal inhibits mast cell activation induced by different stimuli and open a new window for the use of this compound as a mast cell stabilizer.

The antinociceptive and anti-inflammatory action of the CHCl3-soluble phase and its main active component, damnacanthal, isolated from the root of Morinda citrifolia.[Pubmed:21212526]

Biol Pharm Bull. 2011;34(1):103-7.

Morinda citrifolia (Rubiaceae, Noni) is a traditional medicine with various pharmacological activities. We investigated if the MeOH-, CHCl(3)- and BuOH-soluble phase and its main active component, Damnacanthal, isolated from the Noni root, have antinociceptive and anti-inflammatory actions in mice. The CHCl(3)-soluble phase (3 g/kg, per os (p.o.)) significantly reduced pain-related behavior observed in the formalin test. These effects were not suppressed by pretreatment with naloxone (1 mg/kg, intraperitoneally (i.p.)), an opioid receptor antagonist. The CHCl(3)-soluble phase (3 g/kg, p.o.) significantly reduced histamine-induced paw edema. The MeOH- and BuOH-soluble phase had no effect in either test. Furthermore, Damnacanthal (10-100 mg/kg, p.o.) exerted an antinociceptive effect on chemical nociceptive stimuli, and decreased histamine-induced paw edema. Damnacanthal was weakly bound to the histamine H(1) receptor. These data suggest that the CHCl(3)-soluble phase of the Noni root has antinociceptive and anti-inflammatory effects. Furthermore, these effects of Damnacanthal isolated from the Noni root is mediated in part by the histamine H(1) receptor.

Damnacanthal is a potent inducer of apoptosis with anticancer activity by stimulating p53 and p21 genes in MCF-7 breast cancer cells.[Pubmed:24765160]

Oncol Lett. 2014 May;7(5):1479-1484.

Damnacanthal, an anthraquinone compound, is isolated from the roots of Morinda citrifolia L. (noni), which has been used for traditional therapy in several chronic diseases, including cancer. Although noni has long been consumed in Asian and Polynesian countries, the molecular mechanisms by which it exerts several benefits are starting to emerge. In the present study, the effect of Damnacanthal on MCF-7 cell growth regulation was investigated. Treatment of MCF-7 cells with Damnacanthal for 72 h indicated an antiproliferative activity. The MTT method confirmed that Damnacanthal inhibited the growth of MCF-7 cells at the concentration of 8.2 mug/ml for 72 h. In addition, the drug was found to induce cell cycle arrest at the G1 checkpoint in MCF-7 cells by cell cycle analysis. Damnacanthal induced apoptosis, determined by Annexin V-fluorescein isothiocyanate/propidium iodide (PI) dual-labeling, acridine-orange/PI dyeing and caspase-7 expression. Furthermore, Damnacanthal-mediated apoptosis involves the sustained activation of p21, leading to the transcription of p53 and the Bax gene. Overall, the present study provided significant evidence demonstrating that p53-mediated Damnacanthal induced apoptosis through the activation of p21 and caspase-7.

Damnacanthal inhibits the NF-kappaB/RIP-2/caspase-1 signal pathway by inhibiting p56lck tyrosine kinase.[Pubmed:25139491]

Immunopharmacol Immunotoxicol. 2014 Oct;36(5):355-63.

Damnacanthal is a major constituent of Morinda citrifolia L. (noni) and exhibits anti-cancer and anti-inflammatory activities. However, the effects of Damnacanthal on allergic diseases have not been determined. In this study, we investigated the effect of Damnacanthal on mast cell-mediated allergic inflammatory responses. Damnacanthal significantly and dose-dependently inhibited compound 48/80-induced systemic anaphylactic shock, histamine release and intracellular calcium levels. In particular, IgE-mediated passive cutaneous anaphylaxis was significantly inhibited by the oral administration of Damnacanthal. In addition, we report for the first time that p56lck tyrosine kinase was expressed in phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-stimulated mast cells. Furthermore, Damnacanthal inhibited the up-regulation of p56lck tyrosine kinase activity by PMACI and repressed PMACI-induced histidine decarboxylase expression and activity. Damnacanthal also inhibited PMACI-induced interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha expressions by suppressing nuclear factor-kappa B (NF-kappaB) activation and suppressed the activation of caspase-1 and the expression of receptor interacting protein-2. This study shows Damnacanthal inhibits the NF-kappaB/receptor-interacting protein-2/caspase-1 signal pathway by inhibiting p56lck tyrosine kinase and suggests that Damnacanthal has potential for the treatment of mast cell-mediated allergic disorders.

Damnacanthal, a noni anthraquinone, inhibits c-Met and is a potent antitumor compound against Hep G2 human hepatocellular carcinoma cells.[Pubmed:25620570]

Sci Rep. 2015 Jan 26;5:8021.

Damnacanthal, an anthraquinone present in noni plants, targets several tyrosine kinases and has antitumoral effects. This study aims at getting additional insight on the potential of Damnacanthal as a natural antitumor compound. The direct effect of Damnacanthal on c-Met was tested by in vitro activity assays. Additionally, Western blots of c-Met phosphorylation in human hepatocellular carcinoma Hep G2 cells were performed. The antitumor effects of Damnacanthal were tested by using cell growth, soft agar clonogenic, migration and invasion assays. Their mechanisms were studied by Western blot, and cell cycle, apoptosis and zymographic assays. Results show that Damnacanthal targets c-Met both in vitro and in cell culture. On the other hand, Damnacanthal also decreases the phosphorylation levels of Akt and targets matrix metalloproteinase-2 secretion in Hep G2 cells. These molecular effects are accompanied by inhibition of the growth and clonogenic potential of Hep G2 hepatocellular carcinoma cells, as well as induction of Hep G2 apoptosis. Since c-Met has been identified as a new potential therapeutical target for personalized treatment of hepatocellular carcinoma, Damnacanthal and noni extract supplements containing it could be potentially interesting for the treatment and/or chemoprevention of hepatocellular carcinoma through its inhibitory effects on the HGF/c-Met axis.

Immunomodulatory effects of damnacanthal isolated from roots of Morinda elliptica.[Pubmed:20645725]

Pharm Biol. 2010 Apr;48(4):446-52.

Morinda elliptica Ridley (Rubiaceae) has been used traditionally as a medicine to treat various diseases in Malaysia and southeast Asia. In the present study we investigated the immunomodulatory effects of Damnacanthal isolated from the roots of Morinda elliptica. The immunomodulatory effect of this compound was evaluated by using the lymphocyte proliferation assay with mouse thymocytes and human peripheral blood mononuclear cells (PBMC). In addition, the effect of the compound on PBMC cell cycle progression was studied by using flow cytometry. The production of human interleukin-2 and human inteleukin-12 cytokines was also assessed using the enzyme linked immunosorbent assay (ELISA) technique. The lymphocyte proliferation assay showed that Damnacanthal was able to activate mouse thymocytes and PBMC at a low concentration (0.468 microg/mL). Moreover, the production of human interleukin-2 and human interleukin-12 cytokines in the culture supernatant from Damnacanthal activated lymphocytes was markedly up-regulated at 24 h and sustained until 72 h with a slight decrease with time. A positive correlation was found between the level of these two cytokines and the MTT-based proliferation assay. Based on the above results, Damnacanthal can act as an immunomodulatory agent which may be very useful for maintaining a healthy immune system.

Damnacanthal, an effective inhibitor of LIM-kinase, inhibits cell migration and invasion.[Pubmed:24478456]

Mol Biol Cell. 2014 Mar;25(6):828-40.

LIM-kinases (LIMKs) play crucial roles in various cell activities, including migration, division, and morphogenesis, by phosphorylating and inactivating cofilin. Using a bimolecular fluorescence complementation assay to detect the actin-cofilin interaction, we screened LIMK1 inhibitors and identified two effective inhibitors, Damnacanthal (Dam) and MO-26 (a pyrazolopyrimidine derivative). These compounds have already been shown to inhibit Lck, a Src family tyrosine kinase. However, in vitro kinase assays revealed that Dam inhibited LIMK1 more effectively than Lck. Dam suppressed LIMK1-induced cofilin phosphorylation and deceleration of actin retrograde flow in lamellipodia in N1E-115 cells. Dam impaired CXCL12-induced chemotactic migration of Jurkat T lymphocytes and Jurkat-derived, Lck-deficient JCaM1.6 cells and also inhibited serum-induced migration and invasion of MDA-MB-231 breast carcinoma cells. These results suggest that Dam has the potential to suppress cell migration and invasion primarily through the inhibition of LIMK kinase activity. Topical application of Dam also suppressed hapten-induced migration of epidermal Langerhans cells in mouse ears. Dam provides a useful tool for investigating cellular and physiological functions of LIMKs and holds promise for the development of agents against LIMK-related diseases. The bimolecular fluorescence complementation assay system used in this study will provide a useful method to screen for inhibitors of various protein kinases.

Activation of p38 MAPK by damnacanthal mediates apoptosis in SKHep 1 cells through the DR5/TRAIL and TNFR1/TNF-alpha and p53 pathways.[Pubmed:20951126]

Eur J Pharmacol. 2011 Jan 10;650(1):120-9.

The effect of the natural compound Damnacanthal from Morinda citrifolia on SKHep 1 cell growth regulation was investigated. Treatment of SKHep 1 cells with Damnacanthal for 24h indicated a dose-dependent antiproliferative activity. Damnacanthal seems to be selective for tumor cell lines, since there is only minimal toxicity against normal hepatocyte cells (FL83B). This is first demonstration that Damnacanthal-mediated apoptosis involves the sustained activation of the p38 MAPK pathway, leading to the transcription of the death receptor family genes encoding DR5/TRAIL and TNF-R1/TNF-alpha genes as well as the p53-regulated Bax gene. The Damnacanthal-mediated expression of DR5/TRAIL and TNF-R1/TNF-alpha results in caspase 8 activation, leading to Bid cleavage. In turn, activated Bid, acting with p53-regulated Bax, leads to cytochrome c released from mitochondria into the cytoplasm. Combined activation of the death receptors and mitochondrial pathways results in activation of the downstream effecter caspase 3, leading to cleavage of PARP. TRAIL- and TNF-alpha-mediated Damnacanthal-induced apoptosis could be suppressed by treatment with caspase inhibitors as well as soluble death receptors Fc:DR5 and Fc:TNF-R1 chimera. Taken together, this study provided first evidence demonstrating that TRAIL-, TNF-alpha-, and p53-mediated Damnacanthal-induced apoptosis require the activation of p38 MAPK and mitochondrion-mediated caspase-dependent pathways.

Mechanism of damnacanthal-induced [Ca(2+)](i) elevation in human dermal fibroblasts.[Pubmed:10650151]

Eur J Pharmacol. 2000 Jan 10;387(2):119-24.

Damnacanthal is a potent and selective inhibitor of p56(lck) tyrosine kinase in a variety of tissues. We have found, however, using the Ca(2+) microfluorimetry technique, that Damnacanthal releases intracellular Ca(2+) stores and promotes Ca(2+) entry in human dermal fibroblasts. The effect of Damnacanthal on the peak [Ca(2+)](i) values and the latent time to the peak was concentration-dependent. Damnacanthal releases Ca(2+) from thapsigargin-sensitive Ca(2+) stores, and the Ca(2+) stores responding to Damnacanthal were overlapped with those of bradykinin. Damnacanthal-induced Ca(2+) entry was mediated by voltage-dependent and voltage-independent Ca(2+) channels. This effect of Damnacanthal on intracellular Ca(2+) mobilization was also observed in cultured bovine coronary endothelial cells but not demonstrated in freshly isolated rat basilar smooth muscle cells. Our study suggests that Damnacanthal increases intracellular Ca(2+) by releasing Ca(2+) from internal stores and promoting Ca(2+) entry. The relationship between the actions of Damnacanthal on tyrosine kinase and intracellular Ca(2+) requires further investigation.

Damnacanthal is a highly potent, selective inhibitor of p56lck tyrosine kinase activity.[Pubmed:7547985]

Biochemistry. 1995 Sep 26;34(38):12404-10.

Damnacanthal, an anthraquinone isolated from a plant extract, was found to be a potent, selective inhibitor of p56lck tyrosine kinase activity. The structure, potency, and selectivity of Damnacanthal were confirmed by independent synthesis and testing. Damnacanthal exhibited an IC50 of 17 nM for inhibition of p56lck autophosphorylation and an IC50 of 620 nM for phosphorylation of an exogenous peptide by p56lck. Damnacanthal had > 100-fold selectivity for p56lck over the serine/threonine kinases, protein kinase A and protein kinase C, and > 40-fold selectivity for p56lck over four receptor tyrosine kinases. It also demonstrated modest (7-20-fold), but highly statistically significant, selectivity for p56lck over the homologous enzymes p60src and p59fyn. Mechanistic studies demonstrated that Damnacanthal was competitive with the peptide binding site, but mixed noncompetitive with the ATP site. Although Damnacanthal contains a potentially reactive aldehyde moiety, equilibrium dialysis experiments demonstrated that significant amine formation between Damnacanthal and amines occurred only at high concentrations of reactants. However, Damnacanthal appeared to bind nonspecifically to membrane lipids and was not active in whole cell tyrosine kinase assays. Damnacanthal is the most potent, selective inhibitor of p56lck tyrosine kinase activity described to date and may represent the starting point for the identification of novel, selective inhibitors of p56lck which are active in whole cell as well as in cell-free systems.

Induction of normal phenotypes in ras-transformed cells by damnacanthal from Morinda citrifolia.[Pubmed:7693328]

Cancer Lett. 1993 Sep 30;73(2-3):161-6.

We have screened tropical plant extracts for substances that induce normal morphology in K-rasts-NRK cells. As a result we isolated an anthraquinone compound, Damnacanthal, from the chloroform extract of the root of Morinda citrifolia. Damnacanthal induced normal morphology and cytoskeletal structure in K-rasts-NRK cells at the permissive temperature, without changing the amount and localization of Ras. The effect of Damnacanthal was reversible, and the compound had no effect on the morphology of RSVts-NRK cells expressing the src oncogene. Thus, Damnacanthal is a new inhibitor of ras function.

Damnacanthal is an anthraquinone isolated from the root of Morinda citrifolia. Damnacanthal is a highly potent, selective inhibitor of p56lck tyrosine kinase activity. Natural Damnacanthal inhibits p56 lck autophosphorylation and phosphorylation of exogenous substrates with IC50s of 46 nM and 220 nM, respectively. Damnacanthal is a potent inducer of apoptosis with anticancer activity. Damnacanthal also has antinociceptive, anti-inflammatory effects in mice and anti-fungal activity against Candida albicans.

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