Chemopreventive effects of lupulone, a hop {beta}-acid, on human colon cancer-derived metastatic SW620 cells and in a rat model of colon carcinogenesis.
The bitter acids of hops (Humulus lupulus L.) mainly consist of humulones or alpha-acids and lupulones or beta-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 microg/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.
Lamy
Virginie
V
Inserm U682, Laboratoire de Prévention Nutritionnelle du Cancer, Strasbourg, F-67000 France.
Roussi
Stamatiki
S
Chaabi
Mehdi
M
Gossé
Francine
F
Schall
Nicolas
N
Lobstein
Annelise
A
Raul
Francis
F
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001397:Azoxymethane; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D009362:Neoplasm Metastasis; D010539:Permeability; D028321:Plant Preparations / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology* / Q000627:therapeutic use; D019014:fas Receptor / Q000378:metabolism
D016588:Anticarcinogenic Agents; D053222:Fas Ligand Protein; D028321:Plant Preparations; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D013729:Terpenes; D019014:fas Receptor; C008299:lupulon; D001397:Azoxymethane