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Carcinogenesis Advance Access originally published online on April 13, 2007
Carcinogenesis 2007 28(7):1575-1581; doi:10.1093/carcin/bgm080
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Chemopreventive effects of lupulone, a hop ß-acid, on human colon cancer-derived metastatic SW620 cells and in a rat model of colon carcinogenesis

Virginie Lamy1,2,3, Stamatiki Roussi1,2,3, Mehdi Chaabi4,5, Francine Gossé1,2,3, Nicolas Schall1,2,3, Annelise Lobstein4,5 and Francis Raul1,2,3,*

1 Inserm U682, Laboratoire de Prévention Nutritionnelle du Cancer, Strasbourg, F-67000 France
2 Faculté de Médecine, Université Louis Pasteur EA3430, Strasbourg, F-67000 France
3 IRCAD, Strasbourg, F-67000 France
4 CNRS UMR7081, Laboratoire de Pharmacognosie, Illkirch, F-67400 France
5 Faculté de Pharmacie, Université Louis Pasteur, Illkirch, F-67400 France

* To whom correspondence should be addressed. Tel: +33(0)388119023; Fax: +33(0)388119097; Email: francis.raul{at}ircad.u-strasbg.fr

The bitter acids of hops (Humulus lupulus L.) mainly consist of humulones or {alpha}-acids and lupulones or ß-acids. We aimed to evaluate the antiproliferative mechanisms of lupulones on a human metastatic colon carcinoma-derived cell line (SW620 cells) and to assess their chemopreventive effects in a model of colon carcinogenesis. SW620 cell growth was inhibited by 70% after a 48 h exposure to lupulones (40 µg/ml). Lupulones up-regulated the expression of Fas receptor (Fas) and Fas ligand (FasL) as well as TNF-related apoptosis inducing ligand (TRAIL)-R1 (DR4) and -R2 (DR5) receptor proteins, suggesting the involvement of Fas and TRAIL receptors-mediated pathways in lupulone-induced apoptosis. Lupulones also increased the mitochondrial membrane permeability. Colon carcinogenesis was initiated in Wistar rats by intra-peritoneal injections of azoxymethane (AOM), once a week for 2 weeks. One week after the last injection, rats received lupulones (0.001 or 0.005%) in drinking water, and AOM-control rats received the excipient. After 7 months of treatment, the colon of rats receiving 0.001 and 0.005% lupulones showed, respectively, a 30 and a 50% reduction (P < 0.05) of the number of preneoplastic lesions (aberrant crypt foci). In addition, we observed a drastic reduction (70–80%) of the total number of tumors in the colon of rats treated with lupulones when compared with the AOM control group. Lupulones induced apoptosis in SW620 colon-derived metastatic cells by activating both Fas and TRAIL death receptor signaling pathways, and antagonize at a low dose (4 mg/kg/day) colon cancer development. These observations suggest the use of lupulones for colon cancer chemoprevention trials.

Abbreviations: ACF, aberrant crypt foci; AOM, azoxymethane; DMSO, dimethylsulfoxide; Fas, Fas receptor; FasL, Fas ligand; FITC, fluorescein isothiocyanate; PBS, phosphate-buffered saline; TRAIL, TNF-related apoptosis-inducing ligand

Received February 12, 2007; revised March 29, 2007; accepted April 2, 2007.


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