Abstract
There exists a growing body of research which indicates that antimitotics such as taxol and colchicine influence cytokine gene expression. In the present study we examined the effect of podophyllotoxin and six analogs on nuclear factor kappa B (NF-kappa B) activation, and on interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) mRNA expression in human THP-1 monocytes. All compounds were inactive between 0.01μM and 10μM when tested alone. However, podophyllotoxin (0.1 μM) enhanced LPS-induced NF-kappa B activation and IL-1β mRNA expression between 2 and 3-fold. In contrast, LPS-induced TNF-α mRNA expression was decreased between 3 and 6-fold. Comparable results were also observed with the three analogs acetylpodophyllotoxin, 4′-demethylpodophyllotoxin and α-peltatin. The remaining three analogs (podophyllotoxin-4-O-glucoside, β-peltatin-β-D-glucopyransoide and 1,2,3,4-dehydrodesoxypodophyllotoxin) were inactive. Clearly certain structural features such as the presence of a glycosidic group or ring aromatization results in loss of biological activity. Interestingly, the analogs that were inactive in our assays have also been previously shown to lack affinity for tubulin binding. These results suggest that during the initial hours of exposure to podophyllotoxin or specific analogs these compounds do not act as independent stimulants of human monocyte activation, but can selectively enhance or suppress LPS-induced cytokine gene expression.