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Title: A mechanism-based antioxidant approach for the reduction of skin carcinogenesis
Authors: Yunfeng Zhao
Luksana Chaiswing
Terry D. Oberley
Ines Batinic-Haberle
William St. Clair
Charles J. Epstein
Daret St. Clair
University of Kentucky College of Medicine
University of Kentucky
University of Wisconsin Madison
Mahidol University
Duke University
University of California, San Francisco
Keywords: Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 15-Feb-2005
Citation: Cancer Research. Vol.65, No.4 (2005), 1401-1405
Abstract: Studies in our laboratories showed that overexpression of manganese superoxide dismutase (MnSOD) reduced tumor incidence in a multistage skin carcinogenesis mouse model. However, reduction of MnSOD by heterozygous knockout of the MnSOD gene (MnSOD KO) did not lead to an increase in tumor incidence, because a reduction of MnSOD enhanced both cell proliferation and apoptosis. The present study extends our previous studies in the MnSOD KO mice and shows that apoptosis in mouse epidermis occurred prior to cell proliferation (6 versus 24 hours) when treated with tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). To investigate the possibility that a timed administration of SOD following apoptosis but before proliferation may lead to suppression of tumor incidence, we applied a SOD mimetic (MnTE-2-PyP5+) 12 hours after each TPA treatment. Biochemical studies showed that MnTE-2-PyP5+suppressed the level of protein carbonyls and reduced the activity of activator protein-1 and the level of proliferating cellular nuclear antigen, without reducing the activity of p53 or DNA fragmentation following TPA treatment. Histologic examination confirmed that MnTE-2-PyP5+suppressed mitosis without interfering with apoptosis. Remarkably, the incidence and multiplicity of skin tumors were reduced in mice that received MnTE-2-PyP5+before cell proliferation. These results show a novel strategy for an antioxidant approach to cancer intervention.
ISSN: 00085472
Appears in Collections:Scopus 2001-2005

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