Fumagillin Research Articles

Assessment of Oral Albendazole and Fumagillin in the Treatment of Pseudoloma neurophilia in Adult Zebrafish.

Pseudoloma neurophilia (Pn), the causative agent of the most commonly reported disease of zebrafish, is a microsporidianparasite that confounds research by inducing behavioral and physiologic changes in zebrafish. Although a treatmentfor P. neurophilia has not been documented in zebrafish, albendazole (ALB) and fumagillin (FUM) have been used to treatmicrosporidian infections of other fish species. To investigate the efficacy of oral ALB and FUM in the treatment of Pn, weperformed a pilot study that demonstrated the safety and palatability of novel gel-based diets containing FUM or ALB inadult AB zebrafish. In a subsequent study, approximately 250 adult AB zebrafish (previously infected with Pn) were treatedwith these medicated diets for 4 wk. At 4 different time points (weeks 0, 5, 10, and 16 of the study), fish were euthanized andwhole-body qPCR was performed to assess Pn prevalence across treatment and control groups. There was no statisticallysignificant association between treatment group and Pn prevalence at any time point, although potential biologically relevantreductions in Pn prevalence occurred in the combination therapy group at weeks 5 and 16 and in the ALB group at week 5.Based on high-performance liquid chromatography analyses, the medicated diets contained less ALB and more FUM thanexpected, highlighting the importance of validating medicated feed concentrations to ensure safety, efficacy, and consistency.While Pn remains challenging to eradicate and control, results of this study warrant further investigation into the utility ofALB and FUM as potential treatments for this pathogen.

In vitro study on aspects of molecular mechanisms underlying invasive aspergillosis caused by gliotoxin and fumagillin, alone and in combination

Gliotoxin (GT) and fumagillin (FUM) are mycotoxins most abundantly produced by Aspergillus fumigatus during the early stages of infection to cause invasive aspergillosis (IA). Therefore, we hypothesized that GT and FUM could be the possible source of virulence factors, which we put to test adopting in vitro monoculture and the novel integrated multiple organ co-culture (IdMOC) of A549 and L132 cell. We found that (i) GT is more cytotoxic to lung epithelial cells than FUM, and (ii) GT and FUM act synergistically to inflict pathology to the lung epithelial cell. Reactive oxygen species (ROS) is the master regulator of the cytotoxicity of GT, FUM and GT + FUM. ROS may be produced as a sequel to mitochondrial damage and, thus, mitochondria are both the source of ROS and the target to ROS. GT-, FUM- and GT + FUM-induced DNA damage is mediated either by ROS-dependent mechanism or directly by the fungal toxins. In addition, GT, FUM and GT + FUM may induce protein accumulation. Further, it is speculated that GT and FUM inflict epithelial damage by neutrophil-mediated inflammation. With respect to multiple organ cytotoxicity, GT was found to be cytotoxic at IC50 concentration in the following order: renal epithelial cells < type II epithelial cells < hepatocytes < normal lung epithelial cells. Taken together, GT and FUM alone and in combination contribute to exacerbate the damage of lung epithelial cells and, thus, are involved in the progression of IA.

Possible involvement of cyclophilin A processing in fumagillin-induced suppression of cholangiocarcinoma cell proliferation.

Methionine aminopeptidase 2 (MetAP2), a proteolytic enzyme that removes the N-terminal methionine from newly synthesized cellular proteins, plays roles in the development of various cancers and has been found to be over-expressed in cholangiocarcinoma (CCA). Fumagillin, a specific MetAP2 inhibitor, suppresses CCA cell proliferation. In order to determine the molecular mechanisms involved in the suppression of CCA cell proliferation caused by fumagillin, proteomic analysis was performed on fumagillin-treated CCA cells. Proteins affected by fumagillin were analyzed using 2D gel electrophoresis and matrix-assisted laser desorption ionization- time of flight tandem mass spectrometry (MALDI-TOF/TOF). The results showed that the processed form of cyclophilin A (CypA) was greatly decreased in parallel with the suppression of CCA cell proliferation. These results suggest that CypA is possibly a protein substrate of MetAP2 cleavage. Removal of N-terminal methionine by MetAP2 may be essential for proper function of CypA in CCA cell proliferation. MetAP2 and CypA may thus serve as potential therapeutic targets for CCA treatment.

ChemInform Abstract: Fumagillin and Structurally Related Molecules as Source of New Drugs

AbstractReview: 80 refs.

Potential anti‐cancer activity of N‐hydroxy‐7‐(2‐naphthylthio) heptanomide (HNHA), a histone deacetylase inhibitor, against breast cancer both in vitro and in vivo

Histone deacetylase (HDAC) is an attractive target for cancer therapy because it plays a key role in gene expression and carcinogenesis. N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA) is a novel synthetic HDAC inhibitor (HDACI) that shows better pharmacological properties than a known HDACI present in the human fibrosarcoma cell: suberoylanilide hydroxamic acid (SAHA). Here, we investigate the anti-cancer activity of HNHA against breast cancer both in vitro and in vivo. HNHA arrested the cell cycle at the G(1) /S phase via p21 induction, which led to profound inhibition of cancer cell growth in vitro. In addition, HNHA-treated cells showed markedly decreased levels of VEGF and HIF-1α than SAHA and fumagillin (FUMA) when accompanied by increased histone acetylation. HNHA significantly inhibited tumor growth in an in vivo mouse xenograft model. HNHA-treated mice survived significantly longer than SAHA- and FUMA-treated mice. Dynamic MRI showed significantly decreased blood flow in the HNHA-treated mice, implying that HNHA inhibits tumor neovascularization. This finding was accompanied by marked reductions of proangiogenic factors and significant induction of angiogenesis inhibitors in tumor tissues. We have shown that HNHA is an effective anti-tumor agent in breast cancer cells in vitro and in breast cancer xenografts in vivo. Collectively, these findings indicate that HNHA may be a potent anti-cancer agent against breast cancer due to its multi-faceted inhibition of HDAC activity, as well as anti-angiogenesis activity.

Structure of Sch 528647: a new antitumor antibiotic related to fumagillin.

Structure of Sch 528647: a new antitumor antibiotic related to fumagillin.

Synthesis of (−)-Fumagillin

Synthesis of (−)-Fumagillin

Additions and Corrections-The Chemistry of Fumagillin

Additions and Corrections-The Chemistry of Fumagillin

The Chemistry of Fumagillin. IV. The Presence of an Epoxide Grouping and Other Observations on the Nature of the Oxygen Functions1

The Chemistry of Fumagillin. IV. The Presence of an Epoxide Grouping and Other Observations on the Nature of the Oxygen Functions¹

Leukopenia Following Fumagillin Therapy for Amebiasis

Leukopenia Following Fumagillin Therapy for Amebiasis

In vitro and in vivo studies of a new antibiotic, fumagillin, with Endamoeba histolytica.

Summary1. A new antibiotic, fumagillin (“Antibiotic H-3”), was found to be effective in vitro against E. histolytica at concentrations of 1:10,000,000 to 1: 15,000,000. 2. Preliminary in vivo studies on monkeys naturally infected with E. histolytica indicated that fumagillin possesses considerable amebacidal activity. Further investigations are necessary to evaluate this drug more completely.

Fumagillin (H-3), a new antibiotic with amebicidal properties.

Fumagillin (H-3), a new antibiotic with amebicidal properties.