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Enhancement of UVB-Induced Apoptosis by Apigenin in Human Keratinocytes and Organotypic Keratinocyte Cultures

¹ Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas; Departments of ² Pathology and ³ Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, ⁴ Department of Pharmacology and Taxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina; and ⁵ Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

Requests for reprints: Jill C. Pelling, Department of Pathology, Northwestern University, 303 East Superior St., Lurie Building 3-115, Chicago, IL 60611. Phone: 312-503-4848; Fax: 312-503-0386; E-mail: j-pelling{at}northwestern.edu.

Key Words: UVB • apoptosis • keratinocyte • organotypic • apigenin

Topical application of the bioflavonoid 4',5,7-trihydroxyflavone (apigenin) to mouse skin effectively reduces the incidence and size of skin tumors caused by UVB exposure. The ability to act as a chemopreventive compound indicates that apigenin treatment alters the molecular events initiated by UVB exposure; however, the effects of apigenin treatment on UVB-irradiated keratinocytes are not fully understood. In the present study, we have used three models of human keratinocytes to study the effect of apigenin treatment on UVB-induced apoptosis: HaCaT human keratinocyte cells, primary keratinocyte cultures isolated from human neonatal foreskin, and human organotypic keratinocyte cultures. Each keratinocyte model was exposed to a moderate dose of UVB (300–1,000 J/m²), then treated with apigenin (0–50 µmol/L), and harvested to assess apoptosis by Western blot analysis for poly(ADP)ribose polymerase cleavage, annexin-V staining by flow cytometry, and/or the presence of sunburn cells. Apigenin treatment enhanced UVB-induced apoptosis >2-fold in each of the models tested. When keratinocytes were exposed to UVB, apigenin treatment stimulated changes in Bax localization and increased the release of cytochrome c from the mitochondria compared with UVB exposure alone. Overexpression of the antiapoptotic protein Bcl-2 and expression of a dominant-negative form of Fas-associated death domain led to a reduction in the ability of apigenin to enhance UVB-induced apoptosis. These results suggest that enhancement of UVB-induced apoptosis by apigenin treatment involves both the intrinsic and extrinsic apoptotic pathways. The ability of apigenin to enhance UVB-induced apoptosis may explain, in part, the photochemopreventive effects of apigenin. [Cancer Res 2008;68(8):3057–65]

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