(+)-Glaucarubinone

Anti-Tobacco Mosaic Virus Quassinoids from Ailanthus altissima (Mill.) Swingle.[Pubmed:29953225]

J Agric Food Chem. 2018 Jul 18;66(28):7347-7357.

Quassinoids are bitter constituents characteristic of the family Simaroubaceae. A total of 18 C20 quassinoids, including nine new quassinoid glycosides, named chuglycosides A-I (1-6 and 8-10), were identified from the samara of Ailanthus altissima (Mill.) Swingle. All of the quassinoids showed potent anti-tobacco mosaic virus (TMV) activity. A preliminary structure-anti-TMV activity relationship of quassinoids was discussed. The effects of three quassinoids, including chaparrinone (12), (+)-Glaucarubinone (15), and ailanthone (16), on the accumulation of TMV coat protein (CP) were studied by western blot analysis. Ailanthone (16) was further investigated for its influence on TMV spread in the Nicotiana benthamiana plant.

Anti-ageing active ingredients from herbs and nutraceuticals used in traditional Chinese medicine: pharmacological mechanisms and implications for drug discovery.[Pubmed:27659301]

Br J Pharmacol. 2017 Jun;174(11):1395-1425.

Ageing, an unanswered question in the medical field, is a multifactorial process that results in a progressive functional decline in cells, tissues and organisms. Although it is impossible to prevent ageing, slowing down the rate of ageing is entirely possible to achieve. Traditional Chinese medicine (TCM) is characterized by the nourishing of life and its role in anti-ageing is getting more and more attention. This article summarizes the work done on the natural products from TCM that are reported to have anti-ageing effects, in the past two decades. The effective anti-ageing ingredients identified can be generally divided into flavonoids, saponins, polysaccharides, alkaloids and others. Astragaloside, Cistanche tubulosa acteoside, icariin, tetrahydrocurcumin, quercetin, butein, berberine, catechin, curcumin, epigallocatechin gallate, gastrodin, 6-Gingerol, (+)-Glaucarubinone, ginsenoside Rg1, luteolin, icarisid II, naringenin, resveratrol, theaflavin, carnosic acid, catalpol, chrysophanol, cycloastragenol, emodin, galangin, echinacoside, ferulic acid, huperzine, honokiol, isoliensinine, phycocyanin, proanthocyanidins, rosmarinic acid, oxymatrine, piceid, puerarin and salvianolic acid B are specified in this review. Simultaneously, chemical structures of the monomers with anti-ageing activities are listed, and their source, model, efficacy and mechanism are also described. The TCMs with anti-ageing function are classified according to their action pathways, including the telomere and telomerase, the sirtuins, the mammalian target of rapamycin, AMP-activated kinase and insulin/insulin-like growth factor-1 signalling pathway, free radicals scavenging and the resistance to DNA damage. Finally, Chinese compound prescription and extracts related to anti-ageing are introduced, which provides the basis and the direction for the further development of novel and potential drugs. LINKED ARTICLES: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.

Glaucarubinone sensitizes KB cells to paclitaxel by inhibiting ABC transporters via ROS-dependent and p53-mediated activation of apoptotic signaling pathways.[Pubmed:27304668]

Oncotarget. 2016 Jul 5;7(27):42353-42373.

Multidrug resistance (MDR) is considered to be the major contributor to failure of chemotherapy in oral squamous cell carcinoma (SCC). This study was aimed to explore the effects and mechanisms of (+)-Glaucarubinone (GLU), one of the major quassinoids from Simarouba glauca DC, in potentiating cytotoxicity of paclitaxel (PTX), an anticancer drug in KB cells. Our data showed that the administration of GLU pre-treatment significantly enhanced PTX anti-proliferative effect in ABCB1 over-expressing KB cells. The Rh 123 drug efflux studies revealed that there was a significant transport function inhibition by GLU-PTX treatment. Interestingly, it was also found that this enhanced anticancer efficacy of GLU was associated with PTX-induced cell arrest in the G2/M phase of cell cycle. Further, the combined treatment of GLU-PTX had significant decrease in the expression levels of P-gp, MRPs, and BCRP in resistant KB cells at both mRNA and protein levels. Furthermore, the combination treatments showed significant reactive oxygen species (ROS) production, chromatin condensation and reduced mitochondrial membrane potential in resistant KB cells. The results from DNA fragmentation analysis also demonstrated the GLU induced apoptosis in KB cells and its synergy with PTX. Importantly, GLU and/or PTX triggered apoptosis through the activation of pro-apoptotic proteins such as p53, Bax, and caspase-9. Our findings demonstrated for the first time that GLU causes cell death in human oral cancer cells via the ROS-dependent suppression of MDR transporters and p53-mediated activation of the intrinsic mitochondrial pathway of apoptosis. Additionally, the present study also focussed on investigation of the protective effect of GLU and combination drugs in human normal blood lymphocytes. Normal blood lymphocytes assay indicated that GLU is able to induce selective toxicity in cancer cells and in silico molecular docking studies support the choice of GLU as ABC inhibitor to enhance PTX efficacy. Thus, GLU has the potential to enhance the activity of PTX and hence can be a good alternate treatment strategy for the reversal of PTX resistance.

Glaucarubinone Combined with Gemcitabine Improves Pancreatic Cancer Survival in an Immunocompetent Orthotopic Murine Model.[Pubmed:27027695]

J Invest Surg. 2016 Dec;29(6):366-372.

BACKGROUND: Pancreatic cancer continues to have a poor survival rate with an urgent need for improved treatments. (+)-Glaucarubinone, a natural product first isolated from the seeds of the tree Simarouba glauca, has recently been recognized as having anti-cancer properties that may be particularly applicable to pancreatic cancer. METHODS: The effect of (+)-Glaucarubinone on the growth and migration of murine pancreatic cancer cells was assessed by (3)H-thymidine incorporation assay. The survival impact of (+)-Glaucarubinone alone and in combination with gemcitabine chemotherapy was assessed using an immunocompetent orthotopic murine model of pancreatic cancer. RESULTS: (+)-Glaucarubinone inhibited the growth of the murine pancreatic cancer cell lines LM-P and PAN02. Treatment with either (+)-Glaucarubinone or gemcitabine reduced proliferation in vitro and the combination was synergistic. The combination treatment improved survival two-fold compared to gemcitabine treatment alone (p = 0.046) in PAN02 cells. CONCLUSIONS: The synergistic inhibition by (+)-Glaucarubinone and gemcitabine observed in vitro and the improved survival in vivo suggest that (+)-Glaucarubinone may be a useful adjunct to current chemotherapy regimens.

Fundamental studies on the feasibility of deep eutectic solvents for the selective partition of glaucarubinone present in the roots of Simarouba glauca.[Pubmed:26178388]

J Sep Sci. 2015 Sep;38(18):3170-3175.

Several deep eutectic solvents prepared by the complexation of choline chloride as the hydrogen bond acceptor and hydrogen bond donors such as urea, thiourea, ethylene glycol, and glycerol were employed to partition (+)-Glaucarubinone, an antimalarial compound present in roots of the plant, Simarouba glauca. Among all the solvents, the deep eutectic solvent consisting of the mixture of choline chloride and urea the most suitable to partition the antimalarial compound from the extract selectively. Analytical tools such as high-performance liquid chromatography and electrospray ionization mass spectrometry were used for characterizations, and (+)-Glaucarubinone extracted from the roots of the plant by conventional solvent extraction method was used as a reference for comparison. The hydrogen and noncovalent bonds formed between (+)-Glaucarubinone and the deep eutectic solvents could be responsible for the selective partition of the drug molecule.

Glaucarubinone inhibits colorectal cancer growth by suppression of hypoxia-inducible factor 1alpha and beta-catenin via a p-21 activated kinase 1-dependent pathway.[Pubmed:25409929]

Biochim Biophys Acta. 2015 Jan;1853(1):157-65.

p-21-Activated kinase 1 (PAK1) enhances colorectal cancer (CRC) progression by stimulating Wnt/beta-catenin, ERK and AKT pathways. PAK1 also promotes CRC survival via up-regulation of hypoxia-inducible factor 1alpha (HIF-1alpha), a key player in cancer survival. (+)-Glaucarubinone, a quassinoid natural product, inhibits pancreatic cancer growth by down-regulation of PAK1. The aim of this study was to investigate the effect of (+)-Glaucarubinone on CRC growth and metastasis, and the mechanism involved. Cell proliferation was measured in vitro by [(3)H]-thymidine incorporation and in vivo by volume of tumor xenografts. Protein concentrations were measured by Western blotting of cell extracts. We report here that (+)-Glaucarubinone inhibited CRC growth both in vitro and in vivo. The potency of (+)-Glaucarubinone as an inhibitor of cell proliferation was negatively correlated to PAK1 expression in CRC cells. (+)-Glaucarubinone suppressed the expression of HIF-1alpha and beta-catenin. Knockdown of PAK1 by shRNA enhanced inhibition by (+)-Glaucarubinone while constitutively active PAK1 blocked the inhibitory effect. Our findings indicate that (+)-Glaucarubinone inhibited CRC growth by down-regulation of HIF-1alpha and beta-catenin via a PAK1-dependent pathway.

Glaucarubinone and gemcitabine synergistically reduce pancreatic cancer growth via down-regulation of P21-activated kinases.[Pubmed:24491405]

Cancer Lett. 2014 May 1;346(2):264-72.

Pancreatic cancer is one of the most lethal of human malignancies. Nearly 100% cases of pancreatic cancer carry mutations in KRas. P-21-activated kinases (PAKs) are activated by and act downstream of KRas. (+)-Glaucarubinone, a natural product first isolated from the seeds of the tree Simarouba glauca, was originally developed as an antimalarial drug, and has more recently been recognised as an anticancer agent. The aims of this study were to determine whether (+)-Glaucarubinone, alone or in combination with the front-line chemotherapeutic agent gemcitabine, would inhibit the growth of pancreatic cancer cells in vitro or in vivo and the mechanism involved. Growth of the human pancreatic cancer cell lines PANC-1 and MiaPaCa-2 was measured by (3)H-thymidine incorporation in vitro, and by volume as xenografts in SCID mice. The expression and activities of the two serine/threonine kinases PAK1 and PAK4, which are key regulators of cancer progression, were measured by Western blotting. Here we report that (+)-Glaucarubinone decreased proliferation and migration of pancreatic cancer cells in vitro, and reduced their growth as xenografts in vivo. Treatment with (+)-Glaucarubinone and gemcitabine reduced proliferation in vitro and tumor growth in vivo more than treatment with either (+)-Glaucarubinone or gemcitabine alone. Treatment with (+)-Glaucarubinone reduced PAK1 and PAK4 activities, which were further decreased by the combination of (+)-Glaucarubinone and gemcitabine. These results indicate that (+)-Glaucarubinone reduced pancreatic cancer cell growth at least in part via inhibition of pathways involving PAK1 and PAK4. The synergistic inhibition by (+)-Glaucarubinone and gemcitabine observed both in vitro and in vivo suggests that (+)-Glaucarubinone may be a useful adjunct to current regimes of chemotherapy.

Nothospondin, a new AP-1 inhibitory quassinoid from the Cameroonian plant Nothospondias staudtii.[Pubmed:21733691]

Bioorg Med Chem Lett. 2011 Aug 1;21(15):4397-9.

A high throughput screen for inhibitors of the oncogenic transcription factor activator protein-1 (AP-1) was applied to the NCI repository of natural product extracts. The liphophilic extract of the plant Nothospondias staudtii (Simaroubaceae) displayed significant AP-1 inhibition. Bioassay-guided fractionation of the extract lead to a new quassinoid named nothospondin (1), and the known compound (+)-Glaucarubinone (2). The structure of 1 was elucidated by spectroscopic methods. Compounds 1 and 2 showed potent, dose-dependent AP-1 inhibition at noncytotoxic concentrations.

The phytochemical glaucarubinone promotes mitochondrial metabolism, reduces body fat, and extends lifespan of Caenorhabditis elegans.[Pubmed:21264793]

Horm Metab Res. 2011 Apr;43(4):241-3.

Naturally occurring compounds that promote energy expenditure and delay aging in model organisms may be of significant interest, since these substances potentially provide pharmaceutical approaches to tackle obesity and promote healthy lifespan in humans. We aimed to test whether pharmaceutical concentrations of (+)-Glaucarubinone, a cytotoxic and antimalarial quassinoid known from different species of the plant family Simaroubaceae, are capable of affecting metabolism and/or extending lifespan in a nematodal model organism for aging processes, the roundworm Caenorhabditis elegans. Adult C. elegans roundworms, maintained on agar plates, were fed with E. coli strain OP50 bacteria, and (+)-Glaucarubinone was applied to the agar to test (i) whether it alters respiration rates and mitochondrial activity, (ii) whether it affects body fat content, and (iii) whether it may promote longevity by quantifying survival in the presence and absence of the compound. We have found that (+)-Glaucarubinone induces oxygen consumption and reduces body fat content of C. elegans. Moreover and consistent with the concept of mitohormesis, (+)-Glaucarubinone extends C. elegans lifespan when applied at a concentration of 1 or 10 nanomolar. Taken together, (+)-Glaucarubinone is capable of reducing body fat and promoting longevity in C. elegans, tentatively suggesting that this compound may promote metabolic health and lifespan in mammals and possibly humans.

Cytotoxic activity of Brazilian Cerrado plants used in traditional medicine against cancer cell lines.[Pubmed:19501276]

J Ethnopharmacol. 2009 Jun 25;123(3):439-45.

UNLABELLED: The search for new anti-cancer drugs is one of the most prominent research areas of natural products. Numerous active compounds isolated from Brazilian Cerrado plant species have been studied with promising results. AIM OF THE STUDY: To investigate the cytotoxic potential of 412 extracts from Brazilian Cerrado plants used in traditional medicine belonging to 21 families against tumor cell lines in culture. MATERIAL AND METHOD: Maceration of 50 plant species resulted in 412 hexane, dichloromethane, ethanol and hydroalcohol extracts. The cytotoxicity of the extracts was tested against human colon carcinoma (HCT-8), melanoma (MDA-MB-435), and brain (SF-295) tumor cell lines, using the thiazolyl blue test (MTT) assay. Bioassay-guided fractionation was performed for one active extract. RESULTS AND CONCLUSIONS: Twenty-eight of the 412 tested extracts demonstrated a substantial antiproliferative effect, at least 85% inhibition of cell proliferation at 50 microg/mL against one or more cell lines. Those extracts are obtained from different parts of Anacardiaceae, Annonaceae, Apocynaceae, Clusiaceae, Flacourtiaceae, Sapindaceae, Sapotaceae, Simaroubaceae and Zingiberaceae. Complete dose-response curves were generated and IC(50) values were calculated for these active extracts against four cell lines HCT-8, MDA-MB-435, SF-295 and HL-60 (leukemia), and their direct cytotoxic effects were determined. In summary, 14 extracts of 13 species showed toxicity in all tested tumor cell lines, with IC(50) values ranging from 0.1 to 19.1 microg/mL. The strongest cytotoxic activity was found for the hexane extract of Casearia sylvestris var. lingua stem bark, with an IC(50) of 0.1 microg/mL for HCT-8, 0.9 microg/mL for SF-295, 1.2 microg/mL for MDA-MB-435, and 1.3 microg/mL for HL-60, and Simarouba versicolor root bark, with an IC(50) of 0.5 microg/mL for HCT-8, 0.7 microg/mL for SF-295, 1.5 microg/mL for MDA-MB-435, 1.1 microg/mL for HL-60. Bioassay-guided fractionation of the last extract led to the isolation of (+)-Glaucarubinone, which showed pronounced activity against the four cell lines studied. Further studies of the active extracts are necessary for chemical characterization of the active compounds and more extensive biological evaluations.

Quassinoid inhibition of AP-1 function does not correlate with cytotoxicity or protein synthesis inhibition.[Pubmed:19199792]

J Nat Prod. 2009 Mar 27;72(3):503-6.

Several quassinoids were identified in a high-throughput screening assay as inhibitors of the transcription factor AP-1. Further biological characterization revealed that while their effect was not specific to AP-1, protein synthesis inhibition and cell growth assays were inconsistent with a mechanism of simple protein synthesis inhibition. Numerous plant extracts from the plant family Simaroubaceae were also identified in the same screen; bioassay-guided fractionation of one extract (Ailanthus triphylla) yielded two known quassinoids, ailanthinone (3) and (+)-Glaucarubinone (4), which were also identified in the pure compound screening procedure.

Quassinoids from Ailanthus excelsa.[Pubmed:12560029]

Phytochemistry. 2003 Feb;62(4):579-84.

Three quassinoids, 1, 2 and 3, 4-dihydro excelsin 3 were isolated from the stem bark of Ailanthus excelsa, along with five known quassinoids excelsin, glaucarubine, ailanthinone, (+)-Glaucarubinone and glaucarubolone. The glaucarubolone has been isolated for the first time from this plant. The structural elucidation is based on the analysis of spectroscopic data.

Anticancer activity of glaucarubinone analogues.[Pubmed:9778691]

Oncol Res. 1998;10(4):201-8.

A series of (+)-Glaucarubinone analogues, obtained from natural sources as well as synthesized by us, were studied both in vitro and in vivo. The focus of the in vitro assessment was to define solid tumor-selective compounds by quantitating differential cytotoxic activity between murine and human solid tumor cells and either murine leukemia or normal cells. Subsequent in vivo studies were aimed at determining the therapeutic efficacy of these analogues against the murine models. Structure-activity analysis consequent to both the in vitro and in vivo studies demonstrated that few changes could be made in the parent (+)-Glaucarubinone structure (outside of the C-15 position) without abrogating either cytotoxicity or potency. However, significant changes could be made at the C-15 position which modified, either enhanced or diminished, in vitro differential cytotoxicity, potency, human solid tumor selectively, and differential cytotoxicity to a MDR-expressing murine mammary tumor.

Quassinoids exhibit greater selectivity against Plasmodium falciparum than against Entamoeba histolytica, Giardia intestinalis or Toxoplasma gondii in vitro.[Pubmed:8508162]

J Eukaryot Microbiol. 1993 May-Jun;40(3):244-6.

The in vitro activities of a series of quassinoids against Plasmodium falciparum, Entamoeba histolytica, Giardia intestinalis and Toxoplasma gondii have been compared with their in vitro cytotoxic effects against KB cells (human epidermoid carcinoma of the nasopharynx). All of the compounds tested were more toxic to KB cells than to G. intestinalis, but four (ailanthinone, bruceine D, brusatol and (+)-Glaucarubinone) were slightly less toxic to KB cells than to E. histolytica. (+)-Glaucarubinone was similarly more toxic to intracellular T. gondii than to KB cells but ailanthinone was more selective (36 times more toxic to T. gondii than to KB cells). All of the compounds were more toxic to P. falciparum than to KB cells; the most selective quassinoids--glaucarubinone, bruceine D, ailanthinone and brusatol--were found to have toxicity/activity ratios of 285, 76, 48 and 32 respectively. These results suggest that quassinoids have a selective action on P. falciparum. Further studies to elucidate the basis for this are in progress.

In vitro studies on the mode of action of quassinoids with activity against chloroquine-resistant Plasmodium falciparum.[Pubmed:2690830]

Biochem Pharmacol. 1989 Dec 15;38(24):4367-74.

Using the incorporation of [3H]isoleucine or [3H]hypoxanthine into acid-insoluble products as indices of protein- and nucleic acid-synthetic activity, respectively, it was shown that seven plant-derived quassinoids with differing chemical substitutions all inhibited protein synthesis more rapidly than nucleic acid synthesis in human erythrocytes infected with Plasmodium falciparum, in vitro. Five quassinoids (ailanthinone, bruceantin, bruceine B, (+)-Glaucarubinone and holacanthone) were effective within 30 min at doses 10 times their 48 hr in vitro IC50 values. Chaparrin and glaucarubol differed in that they did not inhibit protein synthesis during the time course of these experiments when applied at 10 times their in vitro IC50 values. When these compounds were used at 209 and 114 times their respective IC50 values, their observed effects were identical to those of the other quassinoids studied. The time (t50) at which nucleic acid synthesis was reduced to 50% of control was directly proportional to the t50 for protein synthesis, suggesting that failure of nucleic acid synthesis is a consequence of inhibition of protein synthesis. It is concluded that in the malaria parasite, as in eukaryote models, quassinoids are rapid and potent inhibitors of protein synthesis, and that this is most likely due to effects upon the ribosome, rather than upon nucleic acid metabolism.