Inhibition of mitogen activated protein kinases increases the sensitivity of A549 lung cancer cells to the cytotoxicity induced by a kava chalcone analog

Janel K. Warmka, Eric L. Solberg, Nicholette A. Zeliadt, Balasubramanian Srinivasan, Aaron T. Charlson, Chengguo Xing, Elizabeth V Wattenberg

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

We are interested in investigating the biological activity of chalcones, a major class of compounds found in the beverage kava, in order to develop potent and selective chemopreventive candidates. Consumption of kava in the South Pacific Islands is inversely correlated with cancer incidence, even among smokers. Accordingly, chalcones have anti-cancer activities in animal and cell culture models. To investigate signaling pathways that affect chalcone action we studied a potent analog, (E)-3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (chalcone-24). Chalcone-24 was selected from a series of chalcone analogs that were synthesized based on the structures derived from flavokawain compounds found in kava, and screened in A549 lung cancer cells for induction of cytotoxicity and inhibition of NF-κB, a transcription factor associated with cell survival. Incubation of A549 cells with chalcone-24 resulted in a dose-dependent inhibition of cell viability, inhibition of NF-κB, activation of caspases, and activation of extracellular signal regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK); ERK1/2 and JNK are mitogen activated protein kinases that play central roles in regulating cell fate. Pharmacological inhibitors of ERK1/2 or JNK increased the sensitivity of A549 cells to chalcone-24-induced cytotoxicity, without affecting NF-κB or caspase activity. These results will help refine the synthesis of chalcone analogs to maximize the combination of actions required to prevent and treat cancer.

Original languageEnglish (US)
Pages (from-to)488-492
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume424
Issue number3
DOIs
StatePublished - Aug 3 2012

Bibliographical note

Funding Information:
We thank Ameeta Kelekar and Xazmin Lowman for their assistance with the various assays for cell death. This research was supported by National Institutes of Health grant RO1-CA104609 (E.V.W), a grant from the University of Minnesota AHC Faculty Research Development Program: 2010 (to E.V.W.), National Institutes of Health grant R03-CA125844 (C.X.), and an Engebretson Drug Design & Development Grant 2010 (C.X). These funding sources were not involved in study design; the collection, analysis and interpretation of data; the writing of this report; or the decision to submit this report for publication.

Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.

Keywords

  • A549
  • C-Jun N-terminal kinase
  • Chalcone
  • Extracellular signal regulated kinase
  • Kava
  • Mitogen activated protein kinase

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