The mycotoxin beauvericin induces apoptotic cell death in H4IIE hepatoma cells accompanied by an inhibition of NF-κB-activity and modulation of MAP-kinases.

Beauvericin is a world-spread mycotoxin with a high toxicity in mammalian cells. However, its molecular mechanism of action is not fully understood. Using different cancer cell lines (HepG2, C6, Hct116 and H4IIE), we could show that the cyclic peptide is highly toxic (MTT assay) with IC50 values in low micromolar range. As a molecular mechanism of cell death, necrosis was detected in C6 glioma cells (PI staining), but apoptosis prevails in H4IIE hepatoma cells (caspase 3/7 activity, nuclear fragmentation). In H4IIE cells, beauvericin rapidly decreases the phosphorylation of ERK and strongly increases JNK phosphorylation, while p38 phosphorylation was not affected. Furthermore, a strong inhibition of NF-κB signalling was detectable in H4IIE cells. A screening of 21 protein kinases involved in signal transduction pathways (cell proliferation, survival, angiogenesis and metastasis) showed a selective inhibition of src kinase by beauvericin (IC50=9.8µg/ml). We suggest that beauvericin mediates its toxic effects in H4IIE cells, at least in parts, by a distinct modulation of intracellular signalling molecules.

Enniatins A1, B and B1 from an endophytic strain of Fusarium tricinctum induce apoptotic cell death in H4IIE hepatoma cells accompanied by inhibition of ERK phosphorylation.

Enniatins are mycotoxins which have important impact on human health, e.g. as contaminants of cereals, but also are discussed as possible anticancer agents. We investigated toxic effects of enniatins A1, B and B1 isolated from Fusarium tricinctum on different cancer cell lines. The enniatins showed moderate activity in HepG2 and C6 cells (EC(50)-values approximately 10-25 microM), but were highly toxic in H4IIE cells (EC(50)-values approximately 1-2.5 microM). In H4IIE cells, all enniatins increased caspase 3/7 activity and nuclear fragmentation as markers for apoptotic cell death. Enniatin A1, enniatin B1, and, to a lesser extent, also enniatin B decreased the activation of extracellular regulated protein kinase (ERK) (p44/p42), a mitogen-activated protein kinase which is associated with cell proliferation. Furthermore, enniatins A1 and B1, but not enniatin B were able to inhibit moderately tumor necrosis factor alpha (TNF-alpha)-induced NF-kappaB activation. Screening of 24 additional protein kinases involved in signal transduction pathways (cell proliferation, survival, angiogenesis and metastasis) showed no inhibitory activity of enniatins. We conclude that enniatins A1 and B1 and, to a lesser extent, enniatin B may possess anticarcinogenic properties by induction of apoptosis and disruption of ERK signalling pathway. Further analysis of these substances is necessary to analyse their usefulness for cancer therapy.