Carcinogenesis, Vol. 21, No. 9, 1745-1751,
September 2000
© 2000 Oxford University Press
Carcinogenesis |
The induction of cyclooxygenase-1 by a tobacco carcinogen in U937 human macrophages is correlated to the activation of NF-
B
Laboratory of Cancer Etiology and Chemoprevention, Faculty of Pharmacy, Laval University, Quebec City G1K 7P4, Canada
The nicotine-derived 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), present in tobacco smoke, is most likely involved in lung carcinogenesis in smokers. We demonstrated previously that non-steroidal anti-inflammatory drugs (NSAIDs) inhibit NNK-induced lung tumorigenesis, although the mechanism(s) is unknown. The present study demonstrates that, in U937 human macrophages, cyclooxygenase (COX)-1 and -2 are involved in the bioactivation of NNK to electrophilic mutagenic intermediates. We observed that acetylsalicylic acid and NS-398 decrease COX-dependent NNK activation in U937 cells by 66 and 37%, respectively. NSAIDs also decrease prostaglandin E2 (PGE2) synthesis, which is induced in a dose-dependent manner, reaching a 7-fold increase, in NNK-treated human U937 cells. We observed that NNK induces COX-1 expression and activates the nuclear factor-
B (NF-B), in U937 cells. N-acetyl-L-cysteine and pyrrolidinedithiocarbamate, two inhibitors of reactive oxygen species (ROS), inhibit NNK-induced PGE2 synthesis by 41 and 44%, respectively. These data suggest that ROS, generated during pulmonary metabolism of NNK could act as signal transduction messengers and activate NF-B, which will subsequently induce COX-1 activity and increase PGE2 synthesis. These results reveal a novel aspect of tobacco carcinogenesis, and give us insight into the mechanisms of chemoprevention by NSAIDs. Accordingly, inhibition of NF-B activation, leading to the inhibition of COX, offers a new approach in lung cancer prevention.
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