Abstract
Anethole, a chief constituent of anise, camphor, and fennel, has been shown to block both inflammation and carcinogenesis, but just how these effects are mediated is not known. One possibility is TNF-mediated signaling, which has also been associated with both inflammation and carcinogenesis. In the present report we show that anethole is a potent inhibitor of TNF-induced NF-κB activation (an early response) as monitored by electrophoretic mobility shift assay, IκBα phosphorylation and degradation, and NF-κB reporter gene expression. Suppression of IκBα phosphorylation and NF-κB reporter gene expression induced by TRAF2 and NIK, suggests that anethole acts on IκBα kinase. Anethole also blocked the NF-κB activation induced by a variety of other inflammatory agents. Besides NF-κB, anethole also suppressed TNF-induced activation of the transcription factor AP-1, c-jun N-terminal kinase and MAPK-kinase. In addition, anethole abrogated TNF-induced apoptosis as measured by both caspase activation and cell viability. The anethole analogues eugenol and isoeugenol also blocked TNF signaling. Anethole suppressed TNF-induced both lipid peroxidation and ROI generation. Overall, our results demonstrate that anethole inhibits TNF-induced cellular responses, which may explain its role in suppression of inflammation and carcinogenesis.
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Abbreviations
- ALLN:
-
N-acetylleucylleucylnorleucinal
- DHR123:
-
dihydrorhodamine 123
- DOC:
-
deoxycholate
- FADD:
-
Fas-associated death domain
- FLICE:
-
FADD-like ICE
- IκB:
-
inhibitory subunit of NF-κB
- IκB-DN:
-
IκB-dominant negative
- IKK:
-
IκBα kinase
- EMSA:
-
electrophoretic mobility shift assay
- JNK:
-
c-jun amino terminal kinase
- LPS:
-
lipopolysaccharide
- MDA:
-
malondialdehyde
- MEK:
-
mitogen activated protein kinase kinase
- NE:
-
nuclear extracts
- NIK:
-
NF-κB inducing kinase
- NF-κB:
-
nuclear transcription factor-κB
- OA:
-
okadaic acid
- PMA:
-
phorbol myristate acetate
- PARP:
-
poly (ADP) ribose polymerase
- TRADD:
-
TNF receptor-associated death domain
- TRAF2:
-
TNF receptor-associated factor 2
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Acknowledgements
This research was conducted by The Clayton Foundation for Research. We would like to thank Dr B Darnay and Dr NT Van for assistance with IκBα Western blot analysis and with FACS analysis, respectively.
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Chainy, G., Manna, S., Chaturvedi, M. et al. Anethole blocks both early and late cellular responses transduced by tumor necrosis factor: effect on NF-κB, AP-1, JNK, MAPKK and apoptosis. Oncogene 19, 2943–2950 (2000). https://doi.org/10.1038/sj.onc.1203614
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DOI: https://doi.org/10.1038/sj.onc.1203614
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