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Research Articles: Targets

Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft

¹ Department of Urology, The James and Eilleen Dicke Research Laboratory, Case Western Reserve University; ² University Hospitals of Cleveland; and ³ Case Comprehensive Cancer Center, Cleveland, Ohio

Requests for reprints: Sanjay Gupta, Department of Urology, The James and Eilleen Dicke Research Laboratory, Case Western Reserve University and University Hospitals of Cleveland, 10900 Euclid Avenue, Cleveland, OH 44106. Phone: 216-368-6162; Fax: 216-368-0213. E-mail: sanjay.gupta{at}case.edu

Abstract

Apigenin (4',5,7-trihydroxyflavone) is a promising chemopreventive agent abundantly present in fruits and vegetables that has been shown to promote cell cycle arrest and apoptosis in various malignant cell lines. To determine whether pharmacologic intervention with apigenin has a direct growth inhibitory effect on human prostate tumors implanted in athymic nude mice, we examined cell cycle regulatory molecules as precise molecular targets of apigenin action. Apigenin feeding by gavage to these mice at doses of 20 and 50 µg/mouse/d in 0.2 mL of a vehicle containing 0.5% methyl cellulose and 0.025% Tween 20 resulted in significant decreases in tumor volume and mass of androgen-sensitive 22Rv1 and androgen-insensitive PC-3-implanted cells. Oral intake of apigenin resulted in dose-dependent (a) increase in the protein expression of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18; (b) down-modulation of the protein expression of cyclins D1, D2, and E; and cyclin-dependent kinases (cdk), cdk2, cdk4, and cdk6; (c) decrease in retinoblastoma phosphorylation at serine 780; (d) increase in the binding of cyclin D1 toward WAF1/p21 and KIP1/p27; and (e) decrease in the binding of cyclin E toward cdk2 in both types of tumors. In addition, apigenin feeding resulted in stabilization of p53 by phosphorylation at serine 15 in 22Rv1 tumors, which seems to exhibit p53-dependent growth inhibitory responses. Apigenin intake by these mice also resulted in induction of apoptosis, which positively correlated with serum and tumor apigenin levels. Taken together, this is the first systematic in vivo study showing the involvement of cell cycle regulatory proteins as potential molecular targets of apigenin. [Mol Cancer Ther 2006;5(4):843–52]

Grant support: USPHS grants RO1 CA108512, RO1 AT002709, RO3 CA094248, and RO3 CA099049; Cancer Research and Prevention Foundation (S. Gupta); Athymic Animal Core Facility of the Comprehensive Cancer Center of Case Western Reserve University; and University Hospitals of Cleveland grant P30 CA43703.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/14/05; revised 1/30/06; accepted 2/21/06.