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

Abstract

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.

Lupulone triggers p38 MAPK-controlled activation of p53 and of the TRAIL receptor apoptotic pathway in human colon cancer-derived metastatic cells

“…We also reported a cross-talk between the extrinsic and mitochondrial (intrinsic) apoptotic pathways through a caspase-8 dependent cleavage of Bid protein causing mitochondrial perturbations. However, mitochondrial function was not compromised since no release of cytochrome c was observed (12,14). thus mitochondrial functions remained preserved in lupulone-treated sW620 cells.…”

“…lupulone was obtained from an industrial by-product that contains high amounts of β-acids (carlsberg Breweries A/s, strasbourg, France) and was isolated following the procedure described previously (14).…”

Hop beta acids: Properties, significance and utilization.

“…SW 620 cell growth was inhibited by 70% after a 48 h exposure to lupulones at the dose of 40 µg/ml. Lupulones also increased the mitochondrial membrane permeability (Lamy et al, 2007).…”

“…Růst SW 620 buněk u laboratorních krys byl inhibován o 70 % po 48hodinové expozici beta kyselinami v dávce 40 µg/ml. Beta kyseliny rovněž zvýšily mitochondriální membránovou permeabilitu (Lamy et al, 2007).…”

Utilização de ß-ácidos do lúpulo (Humulus lupulus) em dietas de leitões recém-desmamados

“…Adicionalmente, os α-ácidos do lúpulo têm demonstrado afetar o metabolismo lipídico pelo aumento da β-oxidação de ácidos graxos no fígado e redução do diâmetro de adipócitos e peso do tecido adiposo em camundongos (SUMIYOSHI; . As propriedades sendo atribuídas aos β-ácidos do lúpulo também incluem antiviral (BUCKWOLD et al, 2004), anti-inflamatória (CLEEMPUT et al, 2009TANG et al, 2011), antidepressivo (ZANOLI et al, 2005 e anticâncer (LAMY et al, 2007).…”