Cell lines

breast cancer cell lines (MCF-7 and MDA-MB-231 cells)

Preparation method

The solubility of this compound in DMSO is >10mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

1 nM to 10 μM

Applications

Gliotoxin inhibited proliferation of six breast cancer cell lines in culture and protein prenylation over the same range of concentrations. Treatment with gliotoxin for 24 h led to a clear dose-dependent inhibition of Lamin B farnesylation and Rap1A geranylgeranylation in breast cancer cell lines. Taken together these findings indicated that the observed antitumor activity of gliotoxin in breast cancer cell lines was most likely due to prenyltransferase inhibition.

Animal models

Inbred virgin female (Ludwig/Wistar/Olac) rats bearing tumors induced with N-methyl-Nnitrosourea (NMU)

Dosage form

from 1.25 to 25 mg/kg ; subcutaneous injection; weekly for 4 wk.

Application

In all rats, all five gliotoxin-treated rats completing the study responded to treatment, three of which had >50% tumor regression (partial response) and two others with stable disease (

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

Gliotoxin is an immunosuppressive mycotoxin produced by pathogenic strains of Aspergillus and other fungi with diverse biological activities.[1],[2],[3],[4],[5],[6],[7],[8] It inhibits 20S proteasomal chymotrypsin activity (IC50 = 10 μM), blocking the degradation of IκBα and preventing the activation of NF-κB.[2],[3] Gliotoxin induces apoptosis in monocytes and dendritic cells and reduces phagocytosis by neutrophils.[4],[5]It suppresses viral infection by Nipah and Hendra virus in HEK293T cells (IC50s = 149 and 579 nM, respectively).[6] Under reducing conditions, gliotoxin inhibits leukotriene A4 hydrolase epoxide hydrolase activity, but not aminopeptidase activity, and leukotriene B4 synthesis in neutrophils and monocytes.[7] In vivo, gliotoxin (5 mg/kg) reduces LTB4 plasma levels and blocks peritoneal neutrophil infiltration in a mouse model of peritonitis induced by zymosan A. It also inhibits geranylgeranyltransferase I and farnesyltransferase (IC50s = 17 and 80 μM, respectively).[8]

Reference:
[1]. Kwon-Chung, K.J., and Sugui, J.A. What do we know about the role of gliotoxin in the pathobiology of Aspergillus fumigatus? Med. Mycol. 47(Suppl 1), S97-S103 (2009).
[2]. Kroll, M., Arenzana-Seisdedos, F., Bachelerie, F., et al. The secondary fungal metabolite gliotoxin targets proteolytic activities of the proteasome. Chem. Biol. 6(10), 689-698 (1999).
[3]. Pahl, H.L., Krauss, B., Schulze-Osthoff, K., et al. The immunosuppressive fungal metabolite gliotoxin specifically inhibits transcription factor NF-κB. J. Exp. Med. 183(4), 1829-1840 (1996).
[4]. Anselmi, K., Stolz, D.B., Nalesnik, M., et al. Gliotoxin causes apoptosis and necrosis of rat Kupffer cells in vitro and in vivo in the absence of oxidative stress: Exacerbation by caspase and serine protease inhibition. J. Hepatol. 47(1), 103-113 (2007).
[5]. Orciuolo, E., Stanzani, M., Canestraro, M., et al. Effects of Aspergillus fumigatus gliotoxin and methylprednisolone on human neutrophils: Implications for the pathogenesis of invasive aspergillosis. J. Leukoc. Biol. 82(4), 839-848 (2007).
[6]. Aljofan, M., Sganga, M.L., Lo, M.K., et al. Antiviral activity of gliotoxin, gentian violet and brilliant green against Nipah and Hendra virus in vitro. Virol. J. 6:187, (2009).
[7]. Konig, Pace, S., Pein, H., et al. Gliotoxin from Aspergillus fumigatus abrogates leukotriene B4 formation through inhibition of leukotriene A4 hydrolase. Cell. Chem. Biol. 26(4), 524-534 (2019).
[8]. Vigushin, D.M., Mirsaidi, N., Brooke, G., et al. Gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with antitumor activity against breast cancer in vivo. Med. Oncol. 21(1), 21-30 (2004).