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A Dietary Anthocyanidin Delphinidin Induces Apoptosis of Human Prostate Cancer PC3 Cells In vitro and In vivo: Involvement of Nuclear Factor-B Signaling

Department of Dermatology, University of Wisconsin, Madison, Wisconsin

Requests for reprints: Hasan Mukhtar, Department of Dermatology, University of Wisconsin, Medical Sciences Center, B25, 1300 University Avenue, Madison, WI 53706. Phone: 608-263-3927; Fax: 608-263-5223; E-mail: hmukhtar{at}wisc.edu.

Key Words: Delphinidin • Apoptosis • NF-B • Prostate Cancer

Delphinidin, a major anthocyanidin present in many pigmented fruits and vegetables, possesses antioxidant, anti-inflammatory, and antiangiogenic properties. In this study, we provide evidence that it could be developed as a novel agent against human prostate cancer (PCa). We observed that delphinidin treatment to human PCa LNCaP, C4-2, 22R1, and PC3 cells resulted in a dose-dependent inhibition of cell growth without having any substantial effect on normal human prostate epithelial cells. We selected PC3 cells as a test model system because of their highly aggressive proliferative nature. Delphinidin treatment of cells resulted in a dose-dependent induction of apoptosis and arrest of cells in G₂-M phase. This induction of apoptosis seems to be mediated via activation of caspases because N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluromethylketone significantly reduced apoptosis induced by delphinidin. We also observed that delphinidin treatment of cells resulted in a dose-dependent decrease in (a) phosphorylation of IB kinase (NEMO), (b) phosphorylation of nuclear factor-B (NF-B) inhibitory protein IB, (c) phosphorylation of NF-B/p65 at Ser⁵³⁶ and NF-B/p50 at Ser⁵²⁹, (d) NF-B/p65 nuclear translocation, and (e) NF-B DNA binding activity. Delphinidin administration (2 mg, i.p. thrice weekly) to athymic nude mice implanted with PC3 cells resulted in a significant inhibition of tumor growth. Analysis of tumors from delphinidin-treated mice showed significant decrease in the expression of NF-B/p65, Bcl2, Ki67, and PCNA. Taken together, our data suggest that delphinidin could be developed as an agent against human PCa. [Cancer Res 2008;68(20):8564–72]