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Title: Combined alpha-tocopherol and ascorbic acid protects against smoke-induced lung squamous metaplasia in ferrets

Author
item KIM, YURI S. - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item CHONGVIRIYAPHANA, NALINEE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item LIU, CHUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item RUSSEL, ROBERT M. - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Lung Cancer
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/21/2011
Publication Date: 1/2/2012
Citation: Kim, Y., Chongviriyaphana, N., Liu, C., Russel, R., Wang, X. 2012. Combined alpha-tocopherol and ascorbic acid protects against smoke-induced lung squamous metaplasia in ferrets. Lung Cancer. 75:15-23.

Interpretive Summary: Many studies have shown the benefits of fruits and vegetables on reducing risk of lung cancer, the leading cause of cancer deaths in the United States. Previously, we demonstrated that cigarette smoke exposure-induced lung lesions in ferrets were prevented by a combination of low doses of carotenoids, Vitamin E and Vitamin C. However, the role of a combination of Vitamins E and C, alone in the protective effect on lung tumor development remains to be examined. In the present study, we demonstrated that a combination of Vitamin E (at a dose equivalent to 100 mg/day in humans) and Vitamin C (at a dose equivalent to 210 mg/day in a human) protects against smoke-induced lung lesions. Combined Vitamin E and Vitamin C, treatment partially restored the lowered concentrations of Vitamin A in the lungs of smoke-exposed ferrets to the levels in the control group. This data indicated that the combination of Vitamin E and C alone, showed protective effects against smoke-induced lung lesions through the restoring of Vitamin A levels to normal.

Technical Abstract: Many epidemiological studies show the benefit of fruits and vegetables on reducing risk of lung cancer, the leading cause of cancer death in the United States. Previously, we demonstrated that cigarette smoke exposure (SM)-induced lung lesions in ferrets were prevented by a combination of carotene, -tocopherol (AT), and ascorbic acid (AA). However, the role of a combination of AT and AA alone in the protective effect on lung carcinogenesis remains to be examined. In the present study, we investigated whether the combined AT (equivalent to~100 mg/day in the human) and AA (equivalent to ~210 mg/day) supplementation prevents against SM (equivalent to 1.5 packs of cigarettes/day) induced lung squamous metaplasia in ferrets. Ferrets were treated for 6 weeks in the following three groups (9 ferrets/group): (i) Control (no SM, no AT + AA), (ii) SM alone, and (iii) SM + AT + AA. Results showed that SM significantly decreased concentrations of retinoic acid, AT, and reduced form of AA, not total AA, retinol and retinyl palmitate, in the lungs of ferrets. Combined AT + AA treatment partially restored the lowered concentrations of AT, reduced AA and retinoic acid in the lungs of SM-exposed ferrets to the levels in the control group. Furthermore, the combined AT + AA supplementation prevented SM-induced squamous metaplasia [0 positive/9 total ferrets (0%) vs. 5/8 (62%); p < 0.05] and cyclin D1 expression (p < 0.05) in the ferret lungs, in which both were positively correlated with expression of c-Jun expression. Although there were no significant differences in lung microsomal malondialdehyde (MDA) levels among the three groups, we found a positive correlation between MDA levels and cyclin D1, as well asc-Jun expressions in the lungs of ferrets. These data indicate that the combination of antioxidant AT + AA alone exerts protective effects against SM-induced lung lesions through inhibiting cyclin D1 expression and partially restoring retinoic acid levels to normal.