Apigenin is a plant flavonoid which has been shown to possess significant chemopreventive activity in inhibiting chemically- induced and ultraviolet light-induced skin cancer in the mouse skin model. Although apigenin shows promise as a chemopreventive agent, little is known about its molecular mechanism of action. The investigators' preliminary results indicate that apigenin treatment of cultured keratinocytes produces substantial G2/M cell cycle arrest and inhibition of p34cdc2 kinase activity, the cyclin dependent kinase which regulates G2/M transition in mammalian cells. Additional experiments indicated that apigenin had no effect on steady-state protein levels of p34cdc2 Kinase but may effect the p34cdc2 phosphorylation status. In the present application the investigators propose to test the hypothesis that apigenin acts as a chemopreventive agent in skin by inducing cell cycle arrest at G2/M via inhibition of p34cdc2 kinase, the cyclin dependent kinase which is responsible for the G2/M transition in mammalian cells. The following Aims will test this hypothesis both in vitro and in vivo, in epidermal cells at various stages of tumorigenesis: (1) Aim 1 will investigate whether apigenin arrest keratinocytes in G2/M by affecting the phosphorylation state of p34cdc2 kinase, thereby inhibiting its activity. (2) Aim #2 will study whether apigenin is arresting cells at G2/M by acting at the level of cyclin B, either by (a) inhibiting the accumulation of cyclin B during G2, (b) inhibiting the association of cyclin B with the cyclin-dependent kinase p34cdc2, or (c) promoting the association of a cyclin inhibitor with the cyclin/cyclin-dependent kinase complex. (3) Aim #3 will investigate whether apigenin is able to induce G2/M arrest in keratinocyte cell lines at various stages of tumorigenesis. (4) Aim #4 will employ the UV-B carcinogenesis model in SKH-1 mice to examine whether apigenin treatment of mouse skin can inhibit the growth of skin tumor cells in vivo even after foci of tumor cells are present.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA072987-03
Application #
2668065
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Pelroy, Richard
Project Start
1996-05-01
Project End
2000-02-29
Budget Start
1998-03-06
Budget End
1999-02-28
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Kansas
Department
Family Medicine
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
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Kanski, Jaroslaw; Schoneich, Christian (2005) Protein nitration in biological aging: proteomic and tandem mass spectrometric characterization of nitrated sites. Methods Enzymol 396:160-71
Kanski, Jaroslaw; Behring, Antje; Pelling, Jill et al. (2005) Proteomic identification of 3-nitrotyrosine-containing rat cardiac proteins: effects of biological aging. Am J Physiol Heart Circ Physiol 288:H371-81
Van Dross, Rukiyah T; Hong, Xiaoman; Pelling, Jill C (2005) Inhibition of TPA-induced cyclooxygenase-2 (COX-2) expression by apigenin through downregulation of Akt signal transduction in human keratinocytes. Mol Carcinog 44:83-91
Nauser, Thomas; Koppenol, Willem H; Pelling, Jill et al. (2004) UV photolysis of 3-nitrotyrosine generates highly oxidizing species: a potential source of photooxidative stress. Chem Res Toxicol 17:1227-35
Nauser, Thomas; Pelling, Jill; Schoneich, Christian (2004) Thiyl radical reaction with amino acid side chains: rate constants for hydrogen transfer and relevance for posttranslational protein modification. Chem Res Toxicol 17:1323-8
Yamaguchi, Tamio; Nagao, Shizuko; Wallace, Darren P et al. (2003) Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys. Kidney Int 63:1983-94
Van Dross, Rukiyah; Xue, Yue; Knudson, Alexandra et al. (2003) The chemopreventive bioflavonoid apigenin modulates signal transduction pathways in keratinocyte and colon carcinoma cell lines. J Nutr 133:3800S-3804S

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