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Inhibition of Tumor Promoter-mediated Processes in Mouse Skin and Bovine Lens by Caffeic Acid Phenethyl Ester¹

Departments of Environmental Medicine [K. F., H. W., R. B., J. Y.], Physiology and Biophysics [J. Y., J. A. Z.], and Ophthamology [J. A. Z.], New York University Medical Center, New York, New York 10016-6451; Laboratory for Cancer Research, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08855-0789 [M-T. H., T. F., A. H. C.]; and Institute of Cancer Research, College of Physicians and Surgeons, Columbia University, New York, New York 10032 [D. G.]

Caffeic acid phenethyl ester (CAPE) was isolated from propolis (a product of honeybee hives) that has been used in folk medicine as a potent antiinflammatory agent. CAPE is cytotoxic to tumor and virally transformed but not to normal cells. Our main goal was to establish whether CAPE inhibits the tumor promoter (12-O-tetradecanoylphorbol-13-acetate)-induced processes associated with carcinogenesis. Topical treatment of SENCAR mice with very low doses (0.1–6.5 nmol/topical treatment) of CAPE strongly inhibits the following 12-O-tetradecanoylphorbol-13-acetate-mediated oxidative processes that are considered essential for tumor promotion: (a) polymorphonuclear leukocyte infiltration into mouse skin and ears, as quantified by myeloperoxidase activity; (b) hydrogen peroxide (H₂O₂) production; and (c) formation of oxidized bases in epidermal DNA, as measured by 5-hydroxymethyluracil and 8-hydroxylguanine. A 0.5-nmol dose of CAPE suppresses the oxidative burst of human polymorphonuclear leukocytes by 50%. At higher doses (1–10 µmol), CAPE inhibits edema and ornithine decarboxylase induction in CD-1 and SENCAR mice. Interestingly, we discovered that 12-O-tetradecanoylphorbol-13-acetate-induced H₂O₂ production in bovine lenses also is inhibited by CAPE. Cumulatively, these findings point to CAPE as being a potent chemopreventive agent, which may be useful in combatting diseases with strong inflammatory and/or oxidative stress components, i.e., various types of cancer and possibly cataract development.

¹ Presented in part at the Eighty-Third Annual Meeting of the American Association for Cancer Research, San Diego, CA, 1992 (49). This research was supported by USPHS Grants CA 37858 (K. F.), CA 21111 (D. G.), and CA 49756 (A. C.) from the National Cancer Institute and EY 01340 (J. Z.) from the National Eye Institute (its contents are solely the responsibility of the authors and do not necessarily represent the official views of the USPHS); by National Institute for Environmental Health Sciences Cancer Center Grant ES 00260 (K. F.); by a training grant from the Sackler Institute of Biochemical Sciences, New York University Medical Center, and a Student Award for Fight for Sight, Inc. (J. Y.); by American Cancer Society Grant SIG 13 (D. G.); and by the Lucille P. Markey Charitable Trust (D. G.).

² To whom requests for reprints should be addressed, at Department of Environmental Medicine, New York University Medical Center, 550 First Avenue, New York, NY 10016-6451.

³ Present address: Department of Environmental Health Sciences, University of Alabama at Birmingham, School of Public Health, 503 Tidwell Hall, 720 South 20th Street, UAB Station, Birmingham, AL 35294-0008.

⁴ Present address: Jules Stein Eye Institute, UCLA School of Medicine, 100 Stein Plaza, Los Angeles, CA 90024-7008.

Received 8/28/92. Accepted 1/ 6/93.

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