REGULATION OF ORNITHINE DECARBOXYLASE INDUCTION BY DEGUELIN, A NATURAL PRODUCT CANCER CHEMOPREVENTIVE AGENT

Deguelin, a plant-derived rotenoid, mediates potent chemopreventive re sponses through transcriptional regulation of phorbol ester-induced or nithine decarboxylase (ODC) activity. To explore the mechanism of this effect, the activity of this compound was evaluated with a number of model systems, Using cultured mouse epidermal 308 cells, the steady-st ate levels of both 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ODC mRNA and c-fos were decreased by treatment with deguelin, ODC acti vity was also inhibited by bullatacin and various antimitotic agents ( podophyllotoxin, vinblastine, and colchicine), but only deguelin and b ullatacin were active as inhibitors of ODC levels in a TPA-independent c-Myc-mediated induction system using cultured BALB/c c-MycER cells, These results suggest that antimicrotubule effects, as mediated by rot enone, for example, are not responsible for inhibitory activity facili tated by deguelin, This was confirmed by use of an in vitro model of t ubulin polymerization in which deguelin and a variety of other rotenoi ds were investigated and found to be inactive. As anticipated, however , NADH dehydrogenase was inhibited by these rotenoids. Moreover, inhib ition of this enzyme correlated with a rapid depletion of ATP levels a nd potential to inhibit either TPA-or c-Myc-induced ODC activity, It t herefore seems that deguelin-mediated interference with transient requ irements for elevated energy can inhibit the induction of ODC activity and thereby yield a cancer chemo-preventive response.