© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 20, 1525-1533,
October 17, 2001
© 2001 Oxford University Press
ARTICLE |
Esophageal Cancer Prevention in Zinc-Deficient Rats: Rapid Induction of Apoptosis by Replenishing Zinc
Affiliations of authors: L. Y. Y. Fong, V. T. Nguyen (Department of Microbiology and Immunology, Kimmel Cancer Institute), J. L. Farber (Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College), Thomas Jefferson University, Philadelphia, PA.
Correspondence to: Louise Y. Y. Fong, Ph.D., Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, 1020 Locust St., Rm. 385 JAH, Philadelphia, PA 19107–6799 (e-mail: L_Fong{at}lac.jci.tju.edu).
Background: Nutritional zinc deficiency in rats increases esophageal cell proliferation and the incidence of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumors. Replenishing zinc with a zinc-sufficient diet reduces these effects in zinc-deficient (ZD) rats. We investigated whether apoptosis was involved in the reduction of NMBA-induced esophageal tumors when ZD rats consumed a zinc-sufficient diet. Methods: Weanling rats were fed a ZD diet (zinc at 3–4 ppm) for 5 weeks to establish esophageal cell proliferation, then treated once with NMBA (2 mg/kg body weight), and divided into the following five groups (47–100 per group). One ZD group was fed the ZD diet, and four zinc-replenished (ZR) groups, ZR1, ZR24, ZR72, and ZR432, were fed a zinc-sufficient diet (zinc at 74–75 ppm) beginning 1, 24, 72, and 432 hours, respectively, after NMBA treatment. From 24 hours to 2 weeks after beginning a zinc-sufficient diet, esophagi from all ZR groups were analyzed for apoptosis and cell proliferation; ZD esophagi were the controls. Tumor incidence was determined 15 weeks after zinc replenishment. All statistical tests were two-sided. Results: Zinc replenishment initiated shortly after NMBA treatment effectively reduced esophageal tumorigenesis; 8% (three of 37) of ZR1, 14% (five of 37) of ZR24, 19% (five of 26) of ZR72, and 48% (19 of 40) of ZR432 rats developed esophageal tumors compared with 93% (14 of 15) of ZD animals (all P<.001). Importantly, 24 and 30 hours after zinc replenishment, esophagi had numerous apoptotic cells (% apoptotic cells: 0 hour = 2.9%, 95% confidence interval [CI] = 2.5% to 3.3%; 24 hours = 9.4%, 95% CI = 8.2% to 10.6%), and the expression of the proapoptotic Bax protein doubled. Within 48 hours, the ZR1 epithelium was three to five cell layers thick compared with 10–20 layers before zinc replenishment. Conclusions: Zinc replenishment of NMBA-treated ZD rats rapidly induces apoptosis in esophageal epithelial cells and thereby substantially reduces the development of esophageal cancer.
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