3-hydroxy-4-3--4--5--tetramethoxychalcone and Neoplasms

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Movement; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; G2 Phase Cell Cycle Checkpoints; HeLa Cells; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Kynurenine; Male; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Reactive Oxygen Species; T-Lymphocytes; Tubulin Modulators; Xenograft Model Antitumor Assays

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.

Topics: Cell Survival; Chalcone; Chalcones; Drug Resistance, Neoplasm; Humans; Kava; Lung Neoplasms; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Neoplasms