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Regulation of Ornithine Decarboxylase Induction by Deguelin, a Natural Product Cancer Chemopreventive Agent¹

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy [C. G., S. K. L., J. M. P.], Department of Chemistry, College of Liberal Arts and Sciences [J. W. K., R. M. M.], and Department of Surgical Oncology, College of Medicine [R. G. M., R. C. M., J. M. P.], University of Illinois at Chicago, Chicago, Illinois 60612, and Laboratory of Drug Discovery Research and Development, Developmental Therapeutics Program, Division of Cancer Treatment, Diagnosis, and Centers, National Cancer Institute-Frederick Cancer Research & Development Center, Frederick, Maryland 21702 [E. H.]

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 model systems. Using cultured mouse epidermal 308 cells, the steady-state levels of both 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ODC mRNA and c-fos were decreased by treatment with deguelin. ODC activity was also inhibited by bullatacin and various antimitotic agents (podophyllotoxin, 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 example, 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 found to be inactive. As anticipated, however, NADH dehydrogenase was inhibited by these rotenoids. Moreover, inhibition of this enzyme correlated with a rapid depletion of ATP levels and potential to inhibit either TPA- or 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 chemopreventive response.

¹ Support for this work was provided by Program Project P01 CA48112 funded by the National Cancer Institute. C. G. was supported in part by a Feodor-Lynen Fellowship awarded by the Alexander von Humboldt-Foundation. These data were presented in part at the 87^th Annual Meeting of the AACR, April 20–24, 1996 in Washington, DC (51).

² Present address: German Cancer Research Center, Division 0325, Toxicology and Cancer Risk Factors, Im Neuenheimer Feld 280, D 69120 Heidelberg, Germany.

³ To whom requests for reprints should be addressed, at the Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy. The University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612. Phone: (312) 996-5967; Fax: (312) 996-7107; E-mail: John.M.Pezzuto@uic.edu.

Received 3/13/97. Accepted 6/10/97.

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