Carcinogenesis, Vol 19, 1509-1514, Copyright © 1998 by Oxford University Press
H Wei, R Bowen, X Zhang and M Lebwohl
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.
ARTICLES
Isoflavone genistein inhibits the initiation and promotion of two-stage skin carcinogenesis in mice
Department of Dermatology, Mount Sinai School of Medicine, New York, NY 10029, USA. hw@doc.mssm.edu
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