Oxidative stress and DNA interactions are not involved in Enniatin‐ and Beauvericin‐mediated apoptosis induction

Dornetshuber, R.; Heffeter, Petra; Lemmens‐Gruber, Rosa; Elbling, Leonilla; Marko, Doris; Micksche, M.; Berger, Walter

doi:10.1002/mnfr.200800571

Cited by 64 publications

(53 citation statements)

References 53 publications

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“…This conclusion is supported by a previous study predicting that ROS were not directly involved in enniatin-induced cytotoxic effects. 8 Taking in to account the new knowledge on lysosomal cell death, it is tempting to favor the lysosomal−mitochondrial death pathway. 12,21 Thus, released lysosomal materials could have affected the mitochondria leading to MOMP and the production of ROS.…”

Section: Discussionmentioning

confidence: 99%

Lysosomes as a Possible Target of Enniatin B-Induced Toxicity in Caco-2 Cells

Ivanova

Egge-Jacobsen

Solhaug

et al. 2012

Chem. Res. Toxicol.

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Enniatins are cyclic hexadepsipeptidic mycotoxins with ionophoric, antibiotic, and insecticidal activity. Enniatin B (EnnB), the most important analogue, is produced by many Fusarium species and is a common contaminant in grain-based foods. The compound's cytotoxic potential has been shown in different experiments; however, the mode of action has not been detailed so far. In the present study, several mutually confirmative experiments have been performed indicating that EnnB-initiated cytotoxicity could be connected with lysosomal membrane permeabilization (LMP). Lysosomal functionality, as assessed by the Neutral Red assay, was already affected after 3 h of toxin exposure. After 24 h, cell proliferation was decreased, and there was indication for a cell cycle arrest in the G(2)/M phase leading to the initiation of apoptosis or necrosis. Intracellular ROS-production was observed. However, antioxidants did not alter the observed EnnB-induced loss of lysosomal functionality leading to the conclusion that ROS was not an initial factor but one produced later in the event cascade. The collected data suggested that lysosomal destabilization is an upstream event in EnnB-initiated cytotoxicity followed by a certain extent of translocation of cathepsins into the cytosol, which was observed using immunological and proteomic methods. It appeared that cell death induced by EnnB was delayed and occurred not as a massive lysosomal breakdown but was probably progressing and leading to partial and selective LMP, starting a nonapoptotic cell death pathway with morphological features that had been previously considered as necrotic. The molecular mechanism of EnnB-triggered lysosomal destabilization, and the cellular processes leading to mitochondrial permeabilization and cell death are still unknown. They may, however, be connected to the compound's ionophoric properties.

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Section: Discussionmentioning

confidence: 99%

Lysosomes as a Possible Target of Enniatin B-Induced Toxicity in Caco-2 Cells

Ivanova

Egge-Jacobsen

Solhaug

et al. 2012

Chem. Res. Toxicol.

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“…These report that enniatin- and beauvericin-induced cell death is primarily based on apoptosis induction via the mitochondrial pathway [22,27,28] or necrosis-induction via lysosomal damage [29,30,31]. Contrasting reports have been made regarding enniatin- and beauvericin-induced oxidative stress [32,33,34]. Furthermore, both compounds inhibit the activity of acyl-CoA:cholesterol acyltransferase (ACAT), a protein of the endoplasmic reticulum, which produces cholesteryl esters from cholesterol.…”

Section: Introductionmentioning

confidence: 99%

Effect of Fusarium-Derived Metabolites on the Barrier Integrity of Differentiated Intestinal Porcine Epithelial Cells (IPEC-J2)

Springler

Vrubel²,

Mayer³

et al. 2016

Toxins

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The human, animal and plant pathogen Fusarium, which contaminates agricultural commodities worldwide, produces numerous secondary metabolites. An example is the thoroughly-investigated deoxynivalenol (DON), which severely impairs gastrointestinal barrier integrity. However, to date, the toxicological profile of other Fusarium-derived metabolites, such as enniatins, beauvericin, moniliformin, apicidin, aurofusarin, rubrofusarin, equisetin and bikaverin, are poorly characterized. Thus we examined their effects—as metabolites alone and as metabolites in combination with DON—on the intestinal barrier function of differentiated intestinal porcine epithelial cells (IPEC-J2) over 72 h. Transepithelial electrical resistance (TEER) was measured at 24-h intervals, followed by evaluation of cell viability using neutral red (NR) assay. Enniatins A, A1, B and B1, apicidin, aurofusarin and beauvericin significantly reduced TEER. Moniliformin, equisetin, bikaverin and rubrofusarin had no effect on TEER. In the case of apicidin, aurofusarin and beauvericin, TEER reductions were further substantiated by the addition of otherwise no-effect DON concentrations. In all cases, viability was unaffected, confirming that TEER reductions were not due to compromised viability. Considering the prevalence of mycotoxin contamination and the diseases associated with intestinal barrier disruption, consumption of contaminated food or feed may have substantial health implications.

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“…Dornetschuber et al, demonstrated that Enn cytotoxicity did not involve oxidative stress in HL-60 leukemia cells or cervix carcinoma KB-3-1 cells, or cause DNA damage in the form of DNA intercalation (Dornetshuber et al, 2009a).…”

Section: Introductionmentioning

confidence: 99%

Fusarium mycotoxin enniatin B: Cytotoxic effects and changes in gene expression profile

Jönsson

Jestoi

Anthoni

et al. 2016

Toxicology in Vitro

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The mycotoxin enniatin B, a cyclic hexadepsipeptide produced by the plant pathogen Fusarium, is prevalent in grains and grain-based products in different geographical areas. Although enniatins have not been associated with toxic outbreaks, they have caused toxicity in vitro in several cell lines. In this study, the cytotoxic effects of enniatin B were assessed in relation to cellular energy metabolism, cell proliferation, and the induction of apoptosis in Balb 3T3 and HepG2 cells. The mechanism of toxicity was examined by means of whole genome expression profiling of exposed rat primary hepatocytes. Enniatin B altered cellular energy metabolism and reduced cell proliferation in Balb 3T3 and HepG2 cell lines. Furthermore, the proportion of apoptotic cell populations of Balb 3T3 cells slightly increased. On the other hand, enniatin B caused necrotic cell death in primary hepatocytes. Gene expression studies revealed the alteration of energy metabolism due to effects on mitochondrial organization and function and the assembly of complex I of the electron transport chain.

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Oxidative stress and DNA interactions are not involved in Enniatin‐ and Beauvericin‐mediated apoptosis induction

Cited by 64 publications

References 53 publications

Lysosomes as a Possible Target of Enniatin B-Induced Toxicity in Caco-2 Cells

Lysosomes as a Possible Target of Enniatin B-Induced Toxicity in Caco-2 Cells

Effect of Fusarium-Derived Metabolites on the Barrier Integrity of Differentiated Intestinal Porcine Epithelial Cells (IPEC-J2)

Fusarium mycotoxin enniatin B: Cytotoxic effects and changes in gene expression profile

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