sq-23377 and zileuton

Tepoxalin, a dual inhibitor of cyclooxygenase (CO) and 5-lipoxygenase (5LO) with cytokine modifying activity, is also a potent inhibitor of the transcription factor, nuclear factor kappa B (NF kappa B). NF kappa B is a pleiotropic activator that is involved in the regulation of many genes whose products participate in immune or inflammatory responses. Tepoxalin inhibited in a dose related manner NF kappa B activation by PMA + ionomycin or H2O2 in Jurkat and HeLa cells. TNF-alpha-induced NF kappa B was also inhibited by tepoxalin in HeLa cells, while relatively less marked inhibition was observed in Jurkat cells. Activation of NF kappa B in several monocytic cell lines was also suppressed by tepoxalin. However AP-1 stimulation under the same conditions was not affected by tepoxalin. Other CO, LO inhibitors such as naproxen or zileuton did not inhibit NF kappa B activities. This inhibitory activity of tepoxalin was further illustrated by its suppression of NF kappa B regulated genes such as IL-6 in PMA stimulated human PBL and c-myc in IL-2 dependent T cell lines. Tepoxalin also blocked PMA + ionomycin-induced I kappa B degradation in a time-dependent fashion. The possible mechanism of tepoxalin in NF kappa B activation and its potential clinical application are discussed.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Base Sequence; Cell Line; Chloramphenicol O-Acetyltransferase; Cyclooxygenase Inhibitors; DNA Primers; Gene Expression; HeLa Cells; Humans; Hydroxyurea; Interleukin-6; Ionomycin; Kinetics; Lipoxygenase Inhibitors; Mice; Molecular Sequence Data; Naproxen; NF-kappa B; Oligodeoxyribonucleotides; Polymerase Chain Reaction; Proto-Oncogene Proteins c-myc; Pyrazoles; Recombinant Proteins; Tetradecanoylphorbol Acetate; Transfection; Tumor Cells, Cultured