Fumitremorgin C- Toxicity, Inhibition and Cancer

Wednesday, July 19, 2017

Fumitremorgin C (Tryptoquivaline) is a diketopiperazine secondary metabolite, produces by Aspergillus clavatus (Clardy et al, 1975), Aspergillus fumigatus (Cui et al, 1996) and Neosartorya fischeri (Nielsen et al, 1988).  Related compounds produced by these strains are verruculogen and fumitremorgins A and B.

 

Biological Activity – toxicity, inhibition and cancer

 

Neurotoxicity

Fumitremorgins effect the central nervous system, and cause tremors or convulsions at animals (Yamazaki et al, 1971; Nishiyama and Kuga, 1989). Recent evidences for toxicity of Fumitremorgin in human are not available.

 

Occurrence

Aspergillus and Penicillium strains are a common reason for food contamination. However, only few researches have investigated the occurrence of fumitremorgins in food and feed. One research which examined 39 silage-samples, has found that 69% of the samples were contaminated with Aspergillus fumigatus. Analysis of the fungi isolated has found that most of the strains were producers of mycotoxins, including Fumitremorgin B (59.3% of the strains), Fumitremorgin C (33.3%), Fumigaclavine B (29.6%), Fumigaclavine C (7.4%) and gliotoxin (11.1%). Fifty two percent of the isolated produced more than one toxin. (dos Santos et al, 2003). Other research has found fumitremorgin in native bioaerosols from compost facility (Fischer et al, 1999).

 

Anticancer activity

Fumitremorgin C is a potent and specific inhibitor of Breast cancer resistance protein (BCRP/ABCG2) (Rabindran et al, 2000). It reverses the resistance of S1-M1-3.2 and MCF-7/BCRP cells to multiple anticancer drugs such as mitoxantrone, doxorubicin and topotecan.

In addition, Fumitremorgin C has a synergistic effect with gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, suggesting a crosstalk between EGFR and BCRP (Liu et al, 2006). Fumitremorgin C inhibits also the AKT pathway, which is often activated in glioblastoma (Wang et al, 2008). Unfortunately, the neurotoxicity of Fumitremorgin prevents its use as an anticancer drug (Ahmed-Belkacem et al, 2006). Less toxic analogues of Fumitremorgin C, including Ko 143 and Tryprostatin A, were suggested as potential inhibitors of the BCRP in vivo (Allen et al, 2002; Ahmed-Belkacem et al, 2006; Szolomajer-Csikós et al, 2013).

 

Labs

 

References: 
  1. Inhibitors of cancer cell multidrug resistance mediated by breast cancer resistance protein (BCRP/ABCG2)., Ahmed-Belkacem A, Pozza A, Macalou S, Pérez-Victoria JM, Boumendjel A, Di Pietro A. Anticancer Drugs. (2006) 17:239-43
  2. Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C., Allen JD, van Loevezijn A, Lakhai JM, van der Valk M, van Tellingen O, Reid G, Schellens JH, Koomen GJ, Schinkel AH., Mol Cancer Ther. (2002) 1:417-25.
  3. Tryptoquivaline and tryptoquivalone, two tremorgenic metabolites of Aspergillus clavatus., Clardy J, Springer JP, Buechi G, Matsuo K, Wightman R., J. Am. Chem. Soc., (1975) 97:663–665.
  4. Novel mammalian cell cycle inhibitors, tryprostatins A, B and other diketopiperazines produced by Aspergillus fumigatus. I. Taxonomy, fermentation, isolation and biological properties., Cui CB, Kakeya H, Okada G, Onose R, Osada H., J Antibiot (Tokyo). (1996) 49:527-33.
  5. Isolation and toxigenicity of Aspergillus fumigatus from moldy silage., dos Santos VM, Dorner JW, Carreira F., Mycopathologia. (2003) 156:133-8.
  6. Mycotoxins of Aspergillus fumigatus in pure culture and in native bioaerosols from compost facilities., Fischer GMüller TOstrowski RDott W., Chemosphere. (1999) 38:1745-55.
  7. Cooperative effect of gefitinib and fumitremorgin c on cell growth and chemosensitivity in estrogen receptor alpha negative fulvestrant-resistant MCF-7 cells., Liu H, Cheng D, Weichel AK, Osipo C, Wing LK, Chen B, Louis TE, Jordan VC., Int J Oncol. (2006) 29:1237-46.
  8. Growth of and fumitremorgin production by Neosartorya fischeri as affected by temperature, light, and water activity., Nielsen PVBeuchat LRFrisvad JC., Appl Environ Microbiol. (1988) 54:1504-10.
  9. Central effects of the neurotropic mycotoxin fumitremorgin A in the rabbit (I). Effects on the spinal cord., Nishiyama M1, Kuga T., Jpn J Pharmacol. (1989) 50:167-73.
  10. Fumitremorgin C reverses multidrug resistance in cells transfected with the breast cancer resistance protein., Rabindran SK, Ross DD, Doyle LA, Yang W, Greenberger LM., CancerRes. (2000) 60:47-50.
  11. Synthesis and ABCG2 inhibitory activity of novel fumitremorgin C analogs--specificity and structure activity correlations., Szolomajer-Csikós O, Beéry E, Kósa L, Rajnai Z, Jani M, Hetényi A, Jakab KT, Krajcsi P, Toth GK., Med Chem. (2013) 9:494-509.
  12. Establishment of a luciferase assay-based screening system: fumitremorgin C selectively inhibits cellular proliferation of immortalized astrocytes expressing an active form of AKT., Wang L, Sasai K, Akagi T, Tanaka S., Biochem Biophys Res Commun. (2008) 373:392-6. 
  13. Tremorgenic toxins from Aspergillus fumigatus Fres., Yamazaki M, Suzuki S, Miyaki K., Chem Pharm Bull (Tokyo). (1971) 19:1739-40.