Gliotoxin

The Gliocladium fimbriatum

Gliotoxin is an immunosuppressive agent which synthesized by Aspergillusfumigatus and other pathogenic fungi, inhibiting chymotrypsin-like activity of 20S proteasome.[1]
Gliotoxin shows an activity in inhibition of farnesyltransferase with IC50 value for 80 µM and geranyltransferaseI with IC50 value of 17 µM, which is stimulated interest in the potential antitumor activity of this epidithiodioxopiperazine. Also, with mean ± SD IC50 289 ± 328 µM, gliotoxin will inhibit proliferation of six breast cancer cell. And gliotoxinin ihibites intracellular farnesylation of LaminB and geranylgeranylation of Rap1 A following a dose-dependent manner. [2]
A randomized controlled study, which operated in the N-methyl-N-nitrosourea rat mammary carcinoma model, when 10 animals at 10 mg/kg were administered by subcutaneous injection weekly for 4 wk compared with 10 controls, supporting gliotoxin has antitumor activity apparently in vitro and little toxicity. The single doses can be well tolerated up to 25 mg/kg. [2].
The deficiency of the A. fumigatus mutant in gliotoxin-production resulted in less internalization of A. fumigatus conidia into the A549 cells compared with the wild type strain but an increase of phagocytosis by J774 macrophages., Gliotoxin showed to promote A. fumigatus internalization into A549 cells in a dose-dependent manner but inhibit the macrophage phagocytosis when at the concentrations of 10 to 50 ng/ml which are not cytotoxic to the A549 cells. In addition, gliotoxin is able to stimulate the PLD activity of A549 lung epithelial cells. It is efficient for promoting the internalization of A. fumigatus into the cells by this way. Gliotoxin also blocked the production of ROS in A549 epithelial cells significantly at a concentration range from 10 to 100 ng/ml [3].
References:
1.Pahl HL, Krauss B, Schulze-Osthoff K, et al. The immunosuppressive fungal metabolite gliotoxin specifically inhibits transcription factor NF-kappaB. The Journal of Experimental Medicine, 1996 , 183(4):1829-1840.
2.Vigushin DM, Mirsaidi N, Brooke G, et al. Gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with antitumor activity against breast cancer in vivo. MEDICAL ONCOLOGY, 2004, 21(1):21-30.
3.Jia XD, Chen FY, Pan WH, et al. Gliotoxin promotes Aspergillus fumigatus internalization into type II human pneumocyte A549 cells by inducing host phospholipase D activation. Microbes and infection / Institut Pasteur, 2014, 16(6):491-501.

Gliotoxin Suppresses Macrophage Immune Function by Subverting Phosphatidylinositol 3,4,5-Trisphosphate Homeostasis.[Pubmed:27048806]

MBio. 2016 Apr 5;7(2):e02242.

UNLABELLED: Aspergillus fumigatus, an opportunistic fungal pathogen, spreads in the environment by releasing numerous conidia that are capable of reaching the small alveolar airways of mammalian hosts. In otherwise healthy individuals, macrophages are responsible for rapidly phagocytosing and eliminating these conidia, effectively curbing their germination and consequent invasion of pulmonary tissue. However, under some circumstances, the fungus evades phagocyte-mediated immunity and persists in the respiratory tree. Here, we report thatA. fumigatusescapes macrophage recognition by strategically targeting phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] metabolism through Gliotoxin, a potent immunosuppressive mycotoxin. Time-lapse microscopy revealed that, in response to the toxin, macrophages cease to ruffle, undergo abrupt membrane retraction, and fail to phagocytose large targets effectively. Gliotoxin was found to prevent integrin activation and interfere with actin dynamics, both of which are instrumental for phagocytosis; similar effects were noted in immortalized and primary phagocytes. Detailed studies of the underlying molecular mechanisms of toxicity revealed that inhibition of phagocytosis is attributable to impaired accumulation of PtdIns(3,4,5)P3and the associated dysregulation of downstream effectors, including Rac and/or Cdc42. Strikingly, in response to the diacylglycerol mimetic phorbol 12-myristate 13-acetate, Gliotoxin-treated macrophages reactivate beta integrins, reestablish actin dynamics, and regain phagocytic capacity, despite the overt absence of plasmalemmal PtdIns(3,4,5)P3 Together, our findings identify phosphoinositide metabolism as a critical upstream target of Gliotoxin and also indicate that increased diacylglycerol levels can bypass the requirement for PtdIns(3,4,5)P3signaling during membrane ruffling and phagocytosis. IMPORTANCE: Aspergillus fumigatusis the most frequent cause of human infections in theAspergillusgenus. In immunocompromised populations, invasive aspergillosis (IA) is associated with a mortality rate of up to 90%, and current antifungal therapies have failed to prevent or reverse the infection. Therefore, a deeper understanding of the interactions betweenA. fumigatusand its host is required. In healthy humans, alveolar macrophages can ingest and eliminate fungal spores, thus limiting their germination into mycotoxin-producing hyphae. Our studies reveal that Gliotoxin-the most abundantAspergillusmycotoxin-undermines the ability of phagocytes to carry out their protective functions. By targeting PtdIns(3,4,5)P3signaling and downregulating phagocytic immune defenses, the toxin could also exacerbate polymicrobial infections. Notably, we were able to reverse Gliotoxin toxicity by addition of diacylglycerol analogues, which may provide the basis for therapeutic interventions.

Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model.[Pubmed:28736522]

Front Pharmacol. 2017 Jul 7;8:319.

Deregulation of NOTCH2 signaling is implicated in a wide variety of human neoplasias. The current concept of targeting NOTCH is based on using gamma secretase inhibitors (GSI) to regulate the release of the active NOTCH intracellular domain. However, the clinical outcome of GSI remains unsatisfactory. Therefore we analyzed human solid tumor derived cell lines for their nuclear NOTCH activity and evaluated the therapeutic potential of the NOTCH2 transactivation inhibitor Gliotoxin in comparison to the representative GSI DAPT. Electrophoretic mobility shift assays (EMSA) were used as a surrogate method for the detection of NOTCH/CSL transcription factor complexes. The effect of Gliotoxin on cell viability and its clinical relevance was evaluated in vitro and in a melanoma xenograft mouse model. Cell lines derived from melanoma (518A2), hepatocellular carcinoma (SNU398, HCC-3, Hep3B), and pancreas carcinoma (PANC1) express high amounts of nuclear NOTCH2. Gliotoxin efficiently induced apoptosis in these cell lines whereas the GSI DAPT was ineffective. The specificity of Gliotoxin was demonstrated in the well differentiated nuclear NOTCH negative cell line Huh7, which was resistant to Gliotoxin treatment in vitro. In xenotransplanted 518A2 melanomas, a single day dosing schedule of Gliotoxin was well tolerated without any study limiting side effects. Gliotoxin significantly reduced the tumor volume in early (83 mm(3) vs. 115 mm(3), p = 0.008) as well as in late stage (218 mm(3) vs. 576 mm(3), p = 0.005) tumor models. In conclusion, NOTCH2 appears to be a key target of Gliotoxin in human neoplasias and Gliotoxin deserves further evaluation as a potential therapeutic agent in cancer management.

Gliotoxin Inhibits Proliferation and Induces Apoptosis in Colorectal Cancer Cells.[Pubmed:26445050]

Mar Drugs. 2015 Oct 2;13(10):6259-73.

The discovery of new bioactive compounds from marine natural sources is very important in pharmacological research. Here we developed a Wnt responsive luciferase reporter assay to screen small molecule inhibitors of cancer associated constitutive Wnt signaling pathway. We identified that Gliotoxin (GTX) and some of its analogues, the secondary metabolites from marine fungus Neosartorya pseufofischeri, acted as inhibitors of the Wnt signaling pathway. In addition, we found that GTX downregulated the beta-catenin levels in colorectal cancer cells with inactivating mutations of adenomatous polyposis coli (APC) or activating mutations of beta-catenin. Furthermore, we demonstrated that GTX induced growth inhibition and apoptosis in multiple colorectal cancer cell lines with mutations of the Wnt signaling pathway. Together, we illustrated a practical approach to identify small-molecule inhibitors of the Wnt signaling pathway and our study indicated that GTX has therapeutic potential for the prevention or treatment of Wnt dependent cancers and other Wnt related diseases.

Antituberculosis compounds from a deep-sea-derived fungus Aspergillus sp. SCSIO Ind09F01.[Pubmed:28068839]

Nat Prod Res. 2017 Aug;31(16):1958-1962.

Eleven diketopiperazine and fumiquinazoline alkaloids (1-11) together with a tetracyclic triterpenoid helvolic acid (12) were obtained from the cultures of a deep-sea derived fungus Aspergillus sp. SCSIO Ind09F01. The structures of these compounds (1-12) were determined mainly by the extensive NMR, ESIMS spectra data and by comparison with previously described compounds. Besides, anti-tuberculosis, cytotoxic, antibacterial, COX-2 inhibitory and antiviral activities of these compounds were evaluated. Gliotoxin (3), 12,13-dihydroxy-fumitremorgin C (11) and helvolic acid (12) exhibited very strong anti-tuberculosis activity towards Mycobacterium tuberculosis with the prominent MIC50 values of <0.03, 2.41 and 0.894 muM, respectively, which was here reported for the first time. Meanwhile Gliotoxin also displayed significant selective cytotoxicities against K562, A549 and Huh-7 cell lines with the IC50 values of 0.191, 0.015 and 95.4 muM, respectively.

Gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with antitumor activity against breast cancer in vivo.[Pubmed:15034210]

Med Oncol. 2004;21(1):21-30.

Gliotoxin is a natural mycotoxin with immunosuppressive and antimicrobial activity. Inhibition of farnesyltransferase (IC50 80 microM) and geranylgeranyltransferase I (IC50 17 microM) stimulated interest in the potential antitumor activity of this epidithiodioxopiperazine. Gliotoxin inhibited proliferation of six breast cancer cell lines in culture with mean +/- SD IC50 289 +/- 328 microM (range 38-985 microM); intracellular farnesylation of Lamin B and geranylgeranylation of Rap1A were inhibited in a dose-dependent manner. In randomized controlled studies using the N-methyl-N-nitrosourea rat mammary carcinoma model, Gliotoxin had pronounced antitumor activity in vitro and little systemic toxicity when administered to 10 animals at 10 mg/kg by subcutaneous injection weekly for 4 wk compared with 10 controls. Single doses up to 25 mg/kg were well tolerated. The present studies confirm that Gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with pronounced antitumor activity and favorable toxicity profile against breast cancer in vitro and in vivo.

Gliotoxin and related epipolythiodioxopiperazines.[Pubmed:9304400]

Gen Pharmacol. 1996 Dec;27(8):1311-6.

1. Gliotoxin belongs to the epipolythiodioxopiperazine class of secondary metabolites. These compounds show a diverse range of biological activity including antimicrobial, antifungal and antiviral properties. They also display potent in vitro and in vivo immunomodulating activity. 2. Their properties resulted in a number of early studies designed to exploit their possible chemotherapeutic value, although the general toxicity of most members of this class has precluded clinical use. 3. Most recently, their selective immunosuppressive properties have led to the possibility of ex vivo treatment of tissue to selectively remove immune cells responsible for tissue rejection. The mode of action of Gliotoxin appears to be via covalent interaction to proteins through mixed disulphide formation and Gliotoxin has been shown to inhibit a number of thiol requiring enzymes. 4. Gliotoxin is also a potent inducer of apoptotic cell death in a number of cells. Gliotoxin and other members of this class of toxins may be produced in vivo during the course of fungal infections and contribute to the aetiology of the disease.

Gliotoxin is a secondary metabolite, the most abundant mycotoxin secreted by A. fumigatus, inhibits the phagocytosis of macrophages and the immune functions of other immune cells . Gliotoxin inhibits inducible NF-κB activity by preventing IκB degradation, which consequently induces host-cell apoptosis. Gliotoxin activates PKA and increases intracellular cAMP concentration; modulates actin cytoskeleton rearrangement to facilitate A. fumigatus internalization into lung epithelial cells.

Gliotoxin,67-99-2,Aspergillin,Natural Products,Proteasome, buy Gliotoxin , Gliotoxin supplier , purchase Gliotoxin , Gliotoxin cost , Gliotoxin manufacturer , order Gliotoxin , high purity Gliotoxin