4--methoxychalcone and Lung-Neoplasms

The objective of the studies reported here has been to find novel chemopreventive agents effective against carcinogenesis of the lung. In particular, identification of suppressing agents, i.e., compounds preventing the evolution of the neoplastic process, has been sought. For this purpose, inhibition of pulmonary neoplasia in female A/J mice given the test agent starting one week after the last administration of three doses of benzo[a]pyrene has been employed as the experimental model. Under these conditions, chalcone, 4'-methoxychalcone,myo-inositol, dexamethasone, and "terpeneless" orange oil added to the diet suppressed pulmonary adenoma formation. Chalcone and 4'-methoxychalcone are open chain flavonoids, neither of these compounds occurs naturally, and their mechanism of action is not known. myo-Inositol is a naturally occurring compound of particular interest because of its exceedingly low toxicity. Dexamethasone is a potent glucocorticoid. Amongst its biological properties is the capacity to induce maturation of Type 2 alveolar cells and to stimulate production of surfactant by these cells. "Terpeneless" orange oil is a fraction of orange oil consisting predominantly of compounds with carbonyl or hydroxyl groups. The constituent or constituents responsible for the inhibitory effects observed is not known. The above studies are in an early phase of development and their ramifications remain to be determined.

Topics: Animals; Anticarcinogenic Agents; Chalcone; Chalcones; Dexamethasone; Female; Inositol; Lung Neoplasms; Mice; Mice, Inbred A; Plant Oils

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator for the protection of cells against oxidative and xenobiotic stresses. Recent studies have demonstrated that high constitutive expression of Nrf2 is observed in many types of cancer cells showing resistance to anti-cancer drugs, suggesting that the suppression of overexpressed Nrf2 could be an attractive therapeutic strategy to overcome cancer drug resistance. In the present study, we aimed to find small molecule compounds that enhance the sensitivity of tumor cells to cisplatin induced cytotoxicity by suppressing Nrf2-mediated defense mechanism. A549 lung cancer cells were shown to be more resistant to the anti-cancer drug cisplatin than HEK293 cells, with higher Nrf2 signaling activity; constitutively high amounts of Nrf2-downstream target proteins were observed in A549 cells. Among the three chalcone derivatives 4-methoxy-chalcone (4-MC), hesperidin methylchalcone, and neohesperidin dihydrochalcone, 4-MC was found to suppress transcriptional activity of Nrf2 in A549 cells but to activate it in HEK293 cells. 4-MC was also shown to down-regulate expression of Nrf2 and the downstream phase II detoxifying enzyme NQO1 in A549 cells. The PI3K/Akt pathway was found to be involved in the 4-MC-induced inhibition of Nrf2/ARE activity in A549 cells. This inhibition of Nrf2 signaling results in the accelerated generation of reactive oxygen species and exacerbation of cytotoxicity in cisplatin-treated A549 cells. Taken together, these results suggest that the small molecule compound 4-MC could be used to enhance the sensitivity of tumor cells to the therapeutic effect of cisplatin through the regulation of Nrf2/ARE signaling.

Topics: Antineoplastic Agents; Cell Line, Tumor; Chalcones; Cisplatin; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Lung Neoplasms; NF-E2-Related Factor 2; Oxidative Stress; Reactive Oxygen Species; Signal Transduction