Isoflavone genistein inhibits the initiation and promotion of two-stage skin carcinogenesis in mice.
Isoflavone genistein is a specific inhibitor of protein tyrosine kinase (PTK) and has been shown to have a variety of anticancer activities in cultured cells and animal models. We report here that genistein significantly inhibits 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoyl phorbol-13-acetate (TPA)-promoted skin tumorigenesis in a two-stage carcinogenesis model. In an initiation study, 10 micromol genistein was applied daily to female SENCAR mouse skin for 1 week, followed by initiation with 10 nmol DMBA. Mice were then treated with twice weekly 4 microg TPA. Genistein was shown to reduce tumor incidence and multiplicity in DMBA-initiated skin tumors by approximately 20 (P < 0.05) and 50% (P < 0.01), respectively. Two promotion studies were conducted using CD-1 and SENCAR mice. In experiment 1, CD-1 mice were initiated with 100 nmol DMBA and followed by a twice weekly regimen of 1 and 5 micromol genistein/4 microg TPA. In experiment 2, SENCAR mice were initiated with 10 nmol DMBA and followed by a regimen of 5, 10 and 20 micromol genistein/2 microg TPA. Both studies consistently showed that genistein substantially inhibited TPA-promoted skin tumorigenesis by reducing the tumor multiplicity by approximately 60 and 75%, respectively (P < 0.01). However, the tumor incidence appeared to be less affected. Mechanistic studies showed that genistein inhibited DMBA-induced bulky DNA adduct formation and substantially suppressed TPA-stimulated H2O2 and inflammatory responses in mouse skin by >60% (P < 0.01). In contrast, genistein only exhibited a moderate inhibition of TPA-induced ornithine decarboxylase activity (P > 0.05). Our results suggest that genistein exerts its anti-initiational and anti-promotional effects on skin carcinogenesis probably through blockage of DNA adduct formation and inhibition of oxidative and inflammatory events in vivo.
Wei
H
H
Department of Dermatology, Mount Sinai School of Medicine, New York, NY 10029, USA. hw@doc.mssm.edu
Bowen
R
R
Zhang
X
X
Lebwohl
M
M
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002273:Carcinogens; D018736:DNA Adducts / Q000378:metabolism; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D005260:Female; D019833:Genistein / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control; D009955:Ornithine Decarboxylase / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate
C059444:7,12-dimethylbenz(a)anthracene-DNA adduct; D000970:Antineoplastic Agents; D002273:Carcinogens; D018736:DNA Adducts; D015127:9,10-Dimethyl-1,2-benzanthracene; D006861:Hydrogen Peroxide; D019833:Genistein; D009195:Peroxidase; D011505:Protein-Tyrosine Kinases; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate