title: Inhibition of mitogen activated protein kinases increases the sensitivity of A549 lung cancer cells to the cytotoxicity induced by a kava chalcone analog.
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.
authors: Division of Environmental Health Sciences, School of Public Health, University of Minnesota, MMC 807, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
authors: Janel K
authors: JK
authors: Warmka
authors: Eric L
authors: EL
authors: Solberg
authors: Nicholette A
authors: NA
authors: Zeliadt
authors: Balasubramanian
authors: B
authors: Srinivasan
authors: Aaron T
authors: AT
authors: Charlson
authors: Chengguo
authors: C
authors: Xing
authors: Elizabeth V
authors: EV
authors: Wattenberg
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D002599:Chalcone / Q000494:pharmacology*; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020901:Kava / Q000737:chemistry*; D008175:Lung Neoplasms / Q000201:enzymology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000201:enzymology*
chemical_list: C576272:3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one; D047188:Chalcones; D002599:Chalcone; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4