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.
Wätjen
Wim
W
Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-Universität, Düsseldorf, Germany. wim.waetjen@uni-duesseldorf.de
Debbab
Abdessamad
A
Hohlfeld
Anke
A
Chovolou
Yvonni
Y
Kampkötter
Andreas
A
Edrada
Ru Angelie
RA
Ebel
Rainer
R
Hakiki
Abdelhak
A
Mosaddak
Mahjouba
M
Totzke
Frank
F
Kubbutat
Michael H G
MH
Proksch
Peter
P
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000302:isolation & purification / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation
D000970:Antineoplastic Agents; D047630:Depsipeptides; D016328:NF-kappa B; C100264:enniatins; D048049:Extracellular Signal-Regulated MAP Kinases