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.