A Mechanism-Based Antioxidant Approach for the Reduction of Skin Carcinogenesis

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-PyP 5+ ) 12 hours after each TPA treatment. Biochemical studies showed that MnTE-2-PyP 5+ 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-PyP 5+ suppressed mitosis without interfering with apoptosis. Remarkably, the incidence and multiplicity of skin tumors were reduced in mice that received MnTE-2-PyP 5+ before cell proliferation. These results show a novel strategy for an antioxidant approach to cancer intervention. (Cancer Res 2005; 65(4): 1401-5)

SOD-like activity of Mn(II) β-octabromo-meso-tetrakis(N-methylpyridinium-3-yl)porphyrin equals that of the enzyme itself

“…Our further synthetic efforts in searching for a potential therapeutic based on the SAR led us to Mn(III) ortho N-alkylpyridylporphyrins as the most potent candidates for forwarding them into animal models where superoxide-mediated damage is involved. Thus remarkable effects were observed in cancer, radiation, diabetes, ALS, Alzheimer's disease etc [13][14][15][16][17][18][19][20][21][22][23]. Further, along with our mechanistic studies we observed a dramatic impact of the positive charges of the Mn porphyrin on the O 2 •− dismutation; the rate constants are more than two orders of magnitude higher when compared to the neutral or negatively charged porphyrins [3,4].…”

“…In all previous studies the data obtained with E. coli parallel the trends obtained in in vivo animal model studies [1][2][3][4][5][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]37]. Here we compare the effect of Mn II Br 8 TM-3-PyP 4+ , its metal-free porphyrin HBr 8 TM-3-PyP 3+ , and the para analogue Mn II Br 8 TM-4-PyP 4+ on the aerobic growth of an SOD-deficient E. coli strain.…”

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…It became obvious that the effects observed when using Mn porphyrins were not only the consequence of mere scavenging of ROS=RNS, but that MnPs were also able to modulate ROS=RNS-based signaling pathways. Several articles that followed provided evidence that a potent SOD mimic= ONOO À scavenger, such as MnTE-2-PyP 5þ , can strongly inhibit excessive activation of redox-sensitive cellular transcriptional activity (39,221,222,259,288,322,350).…”

“…Inhibition of redox-controlled cellular transcriptional activity. Mn(III) N-alkylpyridylporphyrins inhibit in vitro and in vivo activation of several redox-controlled transcription factors (TFs), HIF-1a, NF-kB, AP-1, and SP-1 (158,221,222,288,322,350). Although not studied yet, such action may occur with other redox-controlled TFs.…”

“…Skin cancer. In a TPA (12-O-tetradecanoylphorbol-13-acetate) skin cancerigenesis model, MnTE-2-PyP 5þ was applied to skin of MnSOD heterozygous knockout mouse (MnSOD þ=À ) at 5 ng daily, 4 days per week, for 14 weeks (350). Tumor was induced with 7,12-dimethylbenz (a)-anthracene.…”