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Cancer Chemopreventive Activity Mediated by Deguelin, a Naturally Occurring Rotenoid¹

Program for Collaborative Research in the Pharmaceutical Sciences, Department of Medicinal Chemistry and Pharmacognosy [C. G., A. D. K., J. M. P.] and Department of Pharmacy Practice [G. O. U.]. College of Pharmacy, Department of Surgical Oncology [C. F. T., R. C. M., J. M. P.], College of Medicine, and Department of Chemistry [J. W. K., R. M. M.], College of Liberal Arts and Sciences, University of Illinois at Chicago, Chicago, Illinois 60612

Deguelin, a natural product isolated from Mundulea sericea (Leguminosae), was shown previously to mediate strong inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity in cell culture and to reduce the formation of preneoplastic lesions when mouse mammary glands were exposed to 7,12-dimethylbenz(a)anthracene. As reported currently, deguelin was synthesized and evaluated for chemopreventive activity in the two-stage 7,12-dimethylbenz(a)anthracene/TPA skin carcinogenesis model with CD-1 mice and in the N-methylnitrosourea mammary carcinogenesis model with Sprague Dawley rats. In the mouse skin study, deguelin reduced tumor incidence from 60% in the control group to 10% in the group treated with a dose of 33 µg, and multiplicity was reduced from 4.2 in the control group to 0.1 in the treatment group. When the dose was increased 10-fold to 330 µg, no tumors were observed in the treatment group. These results correlated with the potential of deguelin to inhibit TPA-induced mouse epidermal ODC activity. When applied topically as a single dose in a time range of 2 h before to 2 h after TPA treatment, deguelin (384 µg) reduced ODC induction by TPA (6.17 µg) by more than 85%. Time course studies indicated that deguelin (33 µg) inhibited TPA (1.17 µg)-induced ODC activity by 70% without affecting the kinetics of induction over a period of 10 h. Complete inhibition of ODC induction was observed at a dose of 330 µg of deguelin. In the rat mammary tumorigenesis study, intragastric administration of 2 or 4 mg of deguelin/kg of body weight daily, 5 days/week, reduced tumor multiplicity from 6.8 tumors/rat in the control group to 5.1 or 3.2 tumors/animal, respectively. At the 4 mg of deguelin/kg of body weight dose level, the tumor latency period was significantly increased. Tumor incidence, however, was unaffected. These data indicate that deguelin exhibits cancer chemopreventive effects in skin and mammary tumorigenesis models and that additional studies are warranted to characterize the cancer chemopreventive or chemotherapeutic potential of this substance more fully.

¹ Supported by National Cancer Institute Grant P01 CA48112. Presented in part at the 87th Annual Meeting of the American Association for Cancer Research, Washington, DC, April 20–24, 1996 (26).

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 Program for Collaborative Research in the Pharmaceutical Sciences, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (M/C 781), 833 South Wood Street, Chicago, Illinois 60612-7231.

Received 6/10/96. Accepted 6/10/97.

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