Eicosanoids, the oxygenated metabolites of arachidonic acid (AA), mediate a variety of human diseases, such as cancer, inflammation and arthritis. To evaluate the role of eicosanoids in epidermoid carcinoma, the expression of AA metabolizing enzymes, such as lipoxygenases (LOXs) and cyclooxygenases (COXs), was analysed in a human epidermoid carcinoma cell line (A431). These studies revealed overexpression of 12-R-LOX and COX-2 in A431 cells. Baicalein (a 12-LOX inhibitor) and celecoxib (a COX-2 inhibitor) significantly reduced thymidine incorporation, whereas 12-(R)-HETE and 12-(S)-HETE (12-LOX metabolites) and PGE(2) (COX-2 metabolite) significantly enhanced thymidine incorporation, suggesting a role for these enzymes in the regulation of A431 cell proliferation. Further studies on the mechanism of cell death by baicalein and celecoxib revealed that the induction of apoptosis in A431 cells was associated with reduction in the Bcl-2/Bax ratio, release of cytochrome c, activation of caspase-3 and PARP cleavage. The apoptosis induced by baicalein and celecoxib was mediated by down regulation of ERK and PI3K-Akt pathways. Further, 12-(R)-HETE, 12-(S)-HETE and PGE(2) upregulated the p-ERK and p-Akt levels, suggesting the involvement of ERK and Akt pathways in the 12-LOX- and COX-2-mediated regulation of growth in A431 cells. Our findings suggest that 12-R-LOX and COX-2 play a critical role in the regulation of growth in epidermoid carcinoma and that their inhibitors may be of potential therapeutic importance.
A novel series of methyl-2-(substituted benzylideneamino)-3-phenyl propionate (2a-j) derivatives have been synthesized. The title compounds (2a-j) were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 200 mg/kg b.w. Compound 2e exhibited the most promising and significant anti-inflammatory profile while compounds 2b, 2h, 2i, and 2j showed moderate to good inhibitory activity at 2nd and 4th h, respectively. These compounds were also found to have considerable analgesic activity (acetic acid-induced writhing model) and antipyretic activity (yeast-induced pyrexia model). In addition, the tested compounds were also found to possess less degree of ulcerogenic potential as compared to the standard NSAIDs. The synthesized compounds were further evaluated for their inhibitory activity against cyclooxygenase enzyme (COX-1/COX-2), by in vitro colorimetric COX (ovine) inhibitor screening assay method. The results revealed that the compounds 2b, 2e, 2h, 2i, and 2j exhibited selective and effective inhibition against COX-2. In an attempt to understand the ligand-protein interactions in terms of their binding affinity, docking studies were also performed using Molegro Virtual Docker (MVD-2013, 6.0) for the title compounds. It was observed that the binding affinities calculated were in agreement with the experimental IC 50 values.
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