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Anethole blocks both early and late cellular responses transduced by tumor necrosis factor: effect on NF-κB, AP-1, JNK, MAPKK and apoptosis

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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Keywords

  • Anethole
  • TNF
  • NF-κB
  • AP-1
  • JNK
  • Apoptosis

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