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Carcinogenesis Advance Access published online on March 27, 2009
Carcinogenesis, doi:10.1093/carcin/bgp069
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Differential effects of several phytochemicals and their derivatives on murine keratinocytes in vitro and in vivo: implications for skin cancer prevention

Magdalena C. Kowalczyk, Zbigniew Walaszek*, Piotr Kowalczyk, Tatsuya Kinjo, Margaret Hanausek and Thomas J. Slaga

Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, U.S.A

* To whom correspondence should be addressed: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, U.S.A. Tel: +210 567 4216; Fax: +210 567 4226; Email: walaszek{at}uthscsa.edu

The purpose of our study was to investigate in vitro the potential cancer preventive properties of several phytochemicals, i.e., grape seed extract (GSE), resveratrol (RES), ursolic acid (URA), ellagic acid (ELA), lycopene (LYC) and N-acetyl-L-cysteine (NAC) to define the mechanisms by which these compounds may inhibit murine skin carcinogenesis. We measured quenching of peroxyl, superoxide and hydroxyl radicals by these phytochemicals. We also used ATP-bioluminescence, Caspase-Glo 3/7 and P450-Glo (CYP1A1 and CYP1B1) assays to study antiproliferative, proapoptotic, and CYP450 inhibiting effects of the phytochemicals. We next determined their effects on a 4-week inflammatory-hyperplasia assay using 7,12-dimethylbenz[a]anthracene (DMBA)-induced murine skin carcinogenesis model to further understand their mechanism of action. Three murine keratinocyte cell lines, i.e., non-tumorigenic (3PC), papilloma-derived (MT1/2), and squamous cell carcinoma-derived (Ca3/7) cell lines were used in in vitro assays. We have found that GSE, ELA and RES are potent scavengers of peroxyl and superoxide radicals. Statistically significant effects on activities of caspases-3 and -7 were observed only after GSE and URA treatments. All tested compounds protected cells from hydrogen peroxide-induced DNA damage. Using a short term complete carcinogenesis assay, we have found that all selected compounds caused marked decreases of epidermal thickness, and (except RES) reduced percentages of mice with mutation in codon 61 of Ha-ras oncogene. In conclusion, differential effects of tested phytochemicals on events and processes critical for the growth inhibition of keratinocytes in vitro and in vivo, indicate that combinations of tested compounds, may, in the future, better counteract both tumor initiation and tumor promotion/progression.

Received December 18, 2008; revised March 18, 2009; accepted March 21, 2009.


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