Deguelin, a plant-derived rotenoid, mediates potent chemopreventive responses through transcriptional regulation of phorbol ester-induced

Deguelin, a plant-derived rotenoid, mediates potent chemopreventive responses through transcriptional regulation of phorbol ester-induced ornithine decarboxylase (ODC) activity. To explore the mechanism of this effect, the activity of this compound was evaluated with a number of modelsystems.Usingculturedmouseepidermal308cells,thesteady-state levels of both 12-0-tetradecanoylphorbol-13-acetate (TPA)-induced ODC mRNA and c-los were decreased by treatment with deguelin. ODC activity was also inhibited by bullatacin and various antimitotic agents (podophyl lotoxin, vinblastine, and colchicine), but only deguelin and bullatacin 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 rotenone, for exam pie, are not responsible for inhibitory activity facilitated by deguelin. This was confirmed by use of an in vitro model of tubulin polymerization in which deguelin and a variety of other rotenoids were investigated and foundto be inactive.As anticipated,however,NADHdehydrogenasewas inhibited by these rotenoids. Moreover, inhibition of this enzyme corre lated with a rapid depletion of ATP levels and potential to inhibit either TPAor c-Myc-induced ODC activity. It therefore seems that deguelin mediated interference with transient requirements for elevated energy can inhibit the induction of ODC activity and thereby yield a cancer chemo preventiveresponse.