Novel hydrogen sulfide releasing NSAIDs inhibit PAH-induced CYP activity and expression in vitro.

B58

A variety of NSAIDs have been shown to be effective in decreasing the risk of certain cancers. However, chronic treatment with conventional NSAIDs can lead to gut ulceration due to the chronic suppression of COX-1 and subsequent inhibition of mucin secretion in the gut. In addition, selective COX-2 inhibitors such as celecoxib and rofecoxib have recently come under fire for causing an increased risk of thrombosis leading to myocardial infarction and stroke in some patients. These unacceptable side effects have dampened the enthusiasm for NSAIDs as cancer chemopreventive agents. A novel series of redox-modified NSAIDs have been synthesized that may address these side effects. These are a series of compounds that are conventional NSAIDs modified with redox active moieties which reduce the deleterious side effects of the parent compound. Here, we have investigated the effect of two NSAIDs modified with a hydrogen sulfide-releasing moiety, S-Diclofenac, and S-Sulindac. In HepG2 liver and LS180 colon cancer cell lines, both S-Diclofenac and S-Sulindac inhibited TCDD, DMBA and BP-induced EROD activity as well as mRNA expression of the carcinogen activating enzymes, CYP1A1, CYP1B1, and CYP1A2. The mechanism of action for S-Diclofenac was determined to be two-fold: through direct inhibition of the CYP enzymes, as well as through decreased transcriptional activation of the aryl hydrocarbon receptor. In conclusion, S-Diclofenac and S-Sulindac were shown to be promising chemoprevention agents through the inhibition of PAH-induced carcinogen activating enzyme activity and expression mediated by the aryl hydrocarbon receptor in vitro.