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Research Articles: Targets

ß-Escin inhibits colonic aberrant crypt foci formation in rats and regulates the cell cycle growth by inducing p21^waf1/cip1 in colon cancer cells

Department of Medicine, Hem-Onc Section, OU Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Requests for reprints: Chinthalapally V. Rao, OU Cancer Institute, University of Oklahoma Health Sciences Center, 975 Northeast 10th Street, BRC Building, Room 1203, Oklahoma City, OK 73104. Phone: 405-271-3224; Fax: 405-271-3225. E-mail: cv-rao{at}ouhsc.edu

Extracts of Aesculus hippocastanum (horse chestnut) seed have been used in the treatment of chronic venous insufficiency, edema, and hemorrhoids. Most of the beneficial effects of horse chestnut are attributed to its principal component ß-escin or aescin. Recent studies suggest that ß-escin may possess anti-inflammatory, anti-hyaluronidase, and anti-histamine properties. We have evaluated the chemopreventive efficacy of dietary ß-escin on azoxymethane-induced colonic aberrant crypt foci (ACF). In addition, we analyzed the cell growth inhibitory effects and the induction of apoptosis in HT-29 human colon cancer cell line. To evaluate the inhibitory properties of ß-escin on colonic ACF, 7-week-old male F344 rats were fed experimental diets containing 0%, 0.025%, or 0.05% ß-escin. After 1 week, the rats received s.c. injections of azoxymethane (15 mg/kg body weight, once weekly for 2 weeks) or an equal volume of normal saline (vehicle). Rats were continued on respective experimental diets and sacrificed 8 weeks after the azoxymethane treatment. Colons were evaluated histopathologically for ACF. Administration of dietary 0.025% and 0.05% ß-escin significantly suppressed total colonic ACF formation up to 40% (P < 0.001) and 50% (P < 0.0001), respectively, when compared with control diet group. Importantly, rats fed ß-escin showed dose-dependent inhibition (49% to 65%, P < 0.0001) of foci containing four or more aberrant crypts. To understand the growth inhibitory effects, HT-29 human colon carcinoma cell lines were treated with various concentrations of ß-escin and analyzed by flow cytometry for apoptosis and cell cycle progression. ß-Escin treatment in HT-29 cells induced growth arrest at the G₁-S phase, which was associated with the induction of the cyclin-dependent kinase inhibitor p21^WAF1/CIP1, and this correlated with reduced phosphorylation of retinoblastoma protein. Results also indicate that ß-escin inhibited growth of colon cancer cells with either wild-type or mutant p53. This novel feature of ß-escin, a triterpene saponin, may be a useful candidate agent for colon cancer chemoprevention and treatment. [Mol Cancer Ther 2006;5(6):1459–66]

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.

Note: The present address for J. Raju is Department of Biology, University of Waterloo, Waterloo, Ontario, Canada.

Received 11/28/05; revised 3/15/06; accepted 4/13/06.