Chemoprevention Of Colon Cancer Research Articles

S-Adenosylmethionine and Methylthioadenosine Inhibit Cellular FLICE Inhibitory Protein Expression and Induce Apoptosis in Colon Cancer Cells

S-Adenosylmethionine (SAMe) and its metabolite 5'-methylthioadenosine (MTA) inhibit mitogen-induced proliferative response in liver and colon cancer cells. SAMe and MTA are also proapoptotic in liver cancer cells by selectively inducing Bcl-x(S) expression. The aims of this work were to assess whether these agents are proapoptotic in colon cancer cells, and if so, to elucidate the molecular mechanisms. We found that both SAMe and MTA are proapoptotic in HT-29 and RKO cells in a dose- and time-dependent manner. Gene microarray uncovered down-regulation of cellular FLICE inhibitory protein (cFLIP). SAMe and MTA treatment led to a decrease in the mRNA and protein levels of both the long and short cFLIP isoforms. This required de novo RNA synthesis and was associated with activation of procaspase-8, Bid cleavage, and release of cytochrome c from the mitochondria. Inhibiting caspase 8 activity or overexpression of cFLIP protected against apoptosis, whereas supplementing with polyamines did not. SAMe and MTA treatment sensitized RKO cells to tumor necrosis factor alpha-related apoptosis-inducing ligand-induced apoptosis. Although SAMe and MTA are proapoptotic in colon cancer cells, they have no toxic effects in NCM460 cells, a normal colon epithelial cell line. In contrast to liver cancer cells, SAMe and MTA had no effect on Bcl-x(S) expression in colon cancer cells. In conclusion, SAMe and MTA are proapoptotic in colon cancer cells but not normal colon epithelial cells. One molecular mechanism identified is the inhibition of cFLIP expression. SAMe and MTA may be attractive agents in the chemoprevention and treatment of colon cancer.

Modulation of gene expression in eicosapentaenoic acid and docosahexaenoic acid treated human colon adenoma cells

Epidemiological studies suggest that high fish intake is associated with a decreased risk of colorectal cancer which has been linked to the high content of the n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acids (EPA) and docosahexaenoic acid (DHA) in some fish. The aim of the study was to compare the modulation of gene expression in LT97 colon adenoma cells in response to EPA and DHA treatment. Therefore, we used custom-designed cDNA arrays containing probes for 306 genes related to stress response, apoptosis and carcinogenesis and hybridised them with cDNA from LT97 cells which were treated for 10 or 24 h with 50 muM EPA or DHA. There was a marked influence of n-3 PUFA on the expression of several gene types, such as detoxification, cell cycle control, signaling pathways, apoptosis and inflammation. DHA and EPA generally modulated different sets of genes, although a few common effects were noted. In our approach, we used preneoplastic adenoma cells which are a relevant model for target cells of chemoprevention. If verified with real time PCR, these results identify genes and targets for chemoprevention of colon cancer.

Protein Kinase Cβ Is an Effective Target for Chemoprevention of Colon Cancer

Colon cancer develops over a period of 10 to 15 years, providing a window of opportunity for chemoprevention and early intervention. However, few molecular targets for effective colon cancer chemoprevention have been characterized and validated. Protein kinase CbetaII (PKCbetaII) plays a requisite role in the initiation of colon carcinogenesis in a preclinical mouse model by promoting proliferation and increased beta-catenin accumulation. In this study, we test the hypothesis that PKCbetaII is an effective target for colon cancer chemoprevention using enzastaurin (LY317615), a PKCbeta-selective inhibitor, in a mouse model of colon carcinogenesis. We find that enzastaurin potently reduces azoxymethane-induced colon tumor initiation and progression by inhibiting PKCbetaII-mediated tumor cell proliferation and beta-catenin accumulation. Biochemically, enzastaurin reduces expression of the PKCbetaII- and beta-catenin/T-cell factor-regulated genes PKCbetaII, cyclooxygenase II, and vascular endothelial growth factor, three genes implicated in colon carcinogenesis. Our results show that enzastaurin is an effective chemopreventive agent in a mouse model of sporadic colon cancer that significantly reduces both tumor initiation and progression by inhibiting expression of proproliferative genes. Thus, PKCbetaII is an important target for colon cancer chemoprevention and the PKCbeta-selective inhibitor enzastaurin may represent an effective chemopreventive agent in patients at high risk for colon cancer.

Capsaicin induces apoptosis by generating reactive oxygen species and disrupting mitochondrial transmembrane potential in human colon cancer cell lines

Although genetic factors are a well-known cause of colorectal cancer, environmental factors contribute more to its development. Despite advances in the fields of surgery, radiotherapy and chemotherapy, the cure rates for colon cancer have not substantially improved over the past few decades. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the principal pungent ingredient of hot chili pepper, has exhibited an anti-tumor effect in many cell types. However, the mechanisms responsible for the anti-tumor effect of capsaicin are not yet completely understood. In this study, we investigated whether capsaicin induces apoptosis in colon cancer cell lines. Capsaicin decreased cell viability in a dose-dependent manner in Colo320DM and LoVo cells. In addition, capsaicin produced cell morphology changes and DNA fragmentation, decreased the DNA contents, and induced phosphatidylserine translocation, which is a hallmark of apoptotic cell death. We showed that capsaicin-induced apoptosis is associated with an increase in ROS generation and a disruption of the mitochondrial transmenbrane potential. A possible mechanism of capsaicin-induced apoptosis is the activation of caspase 3, a major apoptosis-executing enzyme. Treatment with capsaicin induced a dramatic increase in caspase 3 activity, as assessed by the cleavage of Ac-DEVD-AMC, a fluorogenic substrate. In conclusion, our results clearly showed that capsaicin induced apoptosis in colon cancer cells. Although the actual mechanisms of capsaicin-induced apoptosis remain uncertain, it may be a beneficial agent for colon cancer treatment and chemoprevention.

Natural products and colon cancer: current status and future prospects

Carcinogenesis is a multistage process consisting of initiation, promotion and progression phases. Thus, the multistage sequence of events has many phases for prevention and intervention. Chemoprevention, a novel approach for controlling cancer, involves the use of specific natural products or synthetic chemical agents to reverse, suppress or prevent premalignancy before the development of invasive cancer. Several natural products, such as, grains, nuts, cereals, spices, fruits, vegetables, beverages, medicinal plants and herbs and their various phytochemical constituents including, phenolics, flavonoids, carotenoids, alkaloids, nitrogen containing as well as organosulfur compounds confer protective effects against wide range of cancers including colon cancer. Since diet has an important role in the etiology of colon cancer, dietary chemoprevention received attention for colon cancer prevention. However, identification of an agent with chemopreventive potential requires in vitro studies, efficacy and toxicity studies in animal models before embarking on human clinical trials. A brief introduction about colon cancer and the role of some recent natural products in colon cancer chemoprevention with respect to multiple molecular mechanisms in various in vitro, in vivo and clinical studies are described in this review.

Anti-Inflammatory Implications of the Microbial Transformation of Dietary Phenolic Compounds

Due to the success of therapeutic anti-inflammatory compounds to inhibit, retard, and reverse the development of colon cancer, the identification of dietary compounds as chemopreventives is being vigorously pursued. However, an important factor often overlooked is the metabolic transformation of the food-derived compounds in the gut that may affect their bioactivity. Commonly consumed dietary phenolics (esterified ferulic acid and its 5-5′-linked dimer), which have the potential to undergo predominant microbial transformations (de-esterification, hydrogenation, demethylation, dehydroxylation, and dimer cleavage), were incubated with human microbiota. The metabolites were identified (high-performance liquid chromatography and nuclear magnetic resonance) and confirmed to be present in fresh fecal samples from 4 human volunteers. The potential anti-inflammatory properties were compared by measuring the ability of the parent compounds and their metabolites to modulate prostanoid production in a cell line in which the inflammatory pathways were stimulated following a cytokine-induced insult. The compounds were readily de-esterified and hydrogenated, but no dimer cleavage occurred. Only the monomer underwent demethylation and selective de-hydroxylation. The resultant metabolites had differing effects on prostanoid production ranging from a slight increase to a significant reduction in magnitude. This suggests that the microbial transformation of dietary compounds will have important inflammatory implications in the chemoprevention of colon cancer.

Similar reductions in the risk of human colon cancer by selective and nonselective cyclooxygenase-2 (COX-2) inhibitors

BackgroundEpidemiologic and laboratory investigations suggest that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive effects against colon cancer perhaps due at least in part to their activity against cyclooxygenase-2 (COX-2), the rate-limiting enzyme of the prostaglandin cascade.MethodsWe conducted a case control study of colon cancer designed to compare effects of selective and non-selective COX-2 inhibitors. A total of 326 incident colon cancer patients were ascertained from the James Cancer Hospital, Columbus, Ohio, during 2003–2004 and compared with 652 controls with no history of cancer and matched to the cases at a 2:1 ratio on age, race, and county of residence. Data on the past and current use of prescription and over the counter medications and colon cancer risk factors were ascertained using a standardized risk factor questionnaire. Effects of COX-2 inhibiting agents were quantified by calculating odds ratios (OR) and 95% confidence intervals.ResultsResults showed significant risk reductions for selective COX-2 inhibitors (OR = 0.31, 95% CI = 0.16–0.57), regular aspirin (OR = 0.33, 95% CI = 0.20–0.56), and ibuprofen or naproxen (0.28, 95% CI = 0.15–0.54). Acetaminophen, a compound with negligible COX-2 activity and low dose aspirin (81 mg) produced no significant change in the risk of colon cancer.ConclusionThese results suggest that both non-selective and selective COX-2 inhibitors produce significant reductions in the risk of colon cancer, underscoring their strong potential for colon cancer chemoprevention.

Antiproliferative and apoptosis-inducing effects of maslinic and oleanolic acids, two pentacyclic triterpenes from olives, on HT-29 colon cancer cells

We have previously reported the anticarcinogenic effects of an olive fruit extract composed of pentacyclic triterpenes, the main components of which are maslinic acid (73.25%) and oleanolic acid (25.75%). Here we examined the effects of the individual components on proliferation, necrosis and apoptosis rates by fluorescence-based techniques in human HT-29 colon cancer cells. Oleanolic acid showed moderate antiproliferative activity, with an ec50 of 160.6 (se 10.6) micromol/l, and moderate cytotoxicity at high concentrations ( > or = 250 micromol/l). On the other hand, maslinic acid inhibited cell growth with an ec50 of 101.2 (se 7.8) micromol/l, without necrotic effects. Oleanolic acid, which lacks a hydroxyl group at the carbon 2 position, failed to activate caspase-3 as a prime apoptosis protease. In contrast, maslinic acid increased caspase-3-like activity at 10, 25 and 50 micromol/l by 3-, 3.5- and 5-fold over control cells, respectively. The detection of ROS in the mitochondria, which serve as pro-apoptotic signal, evidenced the different bioactivity of the two triterpenes. Confocal microscopy analysis revealed that maslinic acid generated superoxide anions while oleanolic acid-treated cells did not differ from the control. Completion of apoptosis by maslinic acid was confirmed microscopically by the increase in plasma membrane permeability, and detection of DNA fragmentation. In conclusion, the anticancer activity observed for olive fruit extracts seems to originate from maslinic acid but not from oleanolic acid. Maslinic acid therefore is a promising new compound for the chemoprevention of colon cancers.

Aspirin Should Not Be Promoted for Colon Cancer Prevention: Counterpoint

There is little question that aspirin can decrease the risk of large bowel cancer. A large number of observational studies in humans, both case-control and cohort, consistently show a strong protective effect of aspirin ([1][1]). Importantly, three randomized controlled trials show that aspirin

W1100 Uncoupling of EGFR-Snail Axis in Resistant Tumors During Polyethylene Glycol-Mediated Colon Cancer Chemoprevention

Vitro and In Vivo using the ACF model. Methods: Cell growth inhibition was assayed In Vitro. Apoptosis and cell cycle were scored by Annexin V and PI assays. Protein expression (COX-1,2, Cyclin D1, beta-catenin) was examined by Western blotting. In Vivo, the aberrant crypt foci (ACF) model in rats was performed following injections of DMH (100mg/kg) twice a week for 2 weeks. Results: Table 1: The effect of curcumin and sulindac sulfone on colon cancer cells Table 2: ACF formation in rats Conclusion: Curcumin can synergistically potentiate the growth inhibitory effect of low doses of sulindac sulfone In Vitro and In Vivo. The effect of curcumin and sulindac sulfone on colon cancer cells

S39. Toxicity and long-term problems with Aspirin and NSAID's: The problem

Speakers’ abstracts – Sessions 9 and 10 / ejc supplements 6 No. 3 (2008) 1–40 S39. Toxicity and long-term problems with Aspirin and NSAID’s: The problem F.L. Meyskens * Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA, USA Aspirin and other NSAIDs traditionally have been widely used for the relief of musculoskeletal aches and pains, headaches, and more serious rheumatological indications. In the 1980s and afterwards, experimental data and epidemiology observations suggested that they would be effective chemoprevention agents. However, concern about gastrointestinal toxicity tempered early enthusiasm about usage. The development of cox-2 selective inhibitors that promised reduced gastrointesti- nal toxicity led to many clinical trials for potential chemoprevention of colon and other cancers. Although a decrease in polyp burden (in FAP) and a reduction in the number of sporadic adenomas in at-risk individuals was demonstrated, a largely unexpected increase in serious cardiovascular and cerebrovascular toxicities was unmasked that was dose-response related and nearly caused collapse of the Cox-2 selective industry and branded (unjustifiably) all NSAIDs, except perhaps Aspirin, as unsafe. A major problem in assessing the relative toxicity of various NSAIDs is the most studies are retrospective and dose is frequently ignored. Strikingly, recent assessments of overall outcomes following usage of prophylactic Aspirin for vascular protections suggests that the risk-benefit ratio for 81 mg Aspirin daily is clear while a dose of 325 mg Aspirin daily over the long-term may not be. Two major questions need to be addressed before we can move forward and able to use NSAIDs for chemoprevention in a logical manner: 1. What is the pro-coagulant/anti-coagulant profile of Aspirin and other NSAIDs at a variety of doses? 2. Can large databases (eg Medicare, VA) sort out relative GI and cardiovascular toxicities of the major NSAIDs and inform us in a useful way? Until these questions can be answered, future chemoprevention studies of NSAIDs should probably be confined to individuals at higher risk of cancer. Strategies fro moving Aspirin and NSAIDs forward as potential chemoprevention compounds will be discussed, including the value of dose de-escalation studies and combination trials.

Multi-Target Approaches in Colon Cancer Chemoprevention Based on Systems Biology of Tumor Cell-Signaling

Colorectal cancer is the leading cause of cancer related deaths in the United States. Although it is preventable, thousands of lives are lost each year in the U.S. to colorectal cancer than to breast cancer and AIDS combined. In colon cancer, the formation and progression of precancerous lesions like aberrant crypt foci and polyps is associated with the up-regulation of cycloxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and hydroxy methyl glutaryl CoA reductase (HMG-CoA reductase). The current review will focus on the signaling pathway involving COX-2 and HMG-CoA reductase enzymes and their downstream effectors in signaling mechanism. Cancer cells need huge pools of both cholesterol and isoprenoids to sustain their unlimited growth potential. Cholesterol by modulating caveolae formation regulates several signaling molecules like AKT, IGFR, EGFR and Rho which are involved in cell growth and survival. Cholesterol is also essential for lipid body formation which serves as storage sites for COX-2, eicosanoids and caveolin-1. Experimental studies have identified important mechanisms showing that COX-2, caveolin-1, lipid bodies and prenylated proteins is involved in carcinogenesis. Therefore multi-target, multi-drug approach is the ideal choice for effective colon cancer chemoprevention. This review will give an overview of the two pathways, their signaling networks, and the interactions between the components of the two networks in the activation and regulation of cell signaling involving growth/survival and explain the rationale for colon cancer chemoprevention using COX-2 inhibitors and statins.

Azoxymethane-induced rat aberrant crypt foci: Relevance in studying chemoprevention of colon cancer

The pathogenesis of colon cancer involves sequential and multistep progression of epithelial cells initiated to a cancerous state with defined precancerous intermediaries. Aberrant crypt foci (ACF) represent the earliest identifiable intermediate precancerous lesions during colon carcinogenesis in both laboratory animals and humans. ACF are easily induced by colon-specific carcinogens in rodents and can be used to learn more about the process of colon carcinogenesis. For over two decades, since its first discovery, azoxymethane (AOM)-induced rodent ACF have served as surrogate biomarkers in the screening of various anticarcinogens and carcinogens. Several dietary constituents and phytochemicals have been tested for their colon cancer chemopreventive efficacy using the ACF system. There has been substantial effort in defining and refining ACF in terms of understanding their molecular make-up, and extensive research in this field is currently in progress. In chemoprevention studies, AOM-induced rat ACF have been very successful as biomarkers, and have provided several standardized analyses of data. There have been several studies that have reported that ACF data do not correlate to actual colon tumor outcome, however, and hence there has been an ambiguity about their role as biomarkers. The scope of this mini-review is to provide valuable insights and limitations of AOM-induced rat ACF as biomarkers in colon cancer chemoprevention studies. The role of the dynamics and biological heterogeneity of ACF is critical in understanding them as biomarkers in chemoprevention studies.

Does One Pill a Day Keep the Colonoscopist Away?

Does One Pill a Day Keep the Colonoscopist Away?

β-Ionone inhibits colonic aberrant crypt foci formation in rats, suppresses cell growth, and induces retinoid X receptor-α in human colon cancer cells

Beta-ionone, an end-ring analogue of beta-carotenoid, which is a constituent of vegetables and fruits, has been analyzed for colon cancer chemoprevention and treatment. beta-Ionone induced cell growth inhibition and apoptosis in human colon cancer HCT116 cell line. We tested the in vivo chemopreventive efficacy in rat colon carcinogenesis model using aberrant crypt foci (ACF) as endpoint marker. HCT116 cells treated with subtoxic concentrations of beta-ionone resulted dose-dependent cell growth suppression with G1-S-phase growth arrest and significant induction of apoptosis. beta-Ionone up-regulated expression of retinoid X receptor-alpha mRNA dose-dependently in HCT116 cells. To evaluate inhibitory properties of beta-ionone on colonic ACF, 7-week-old male F344 rats were fed experimental diets containing 0%, 0.1%, or 0.2% beta-ionone. After 1 week, rats received s.c. injections of azoxymethane, 15 mg/kg body weight, once weekly for 2 weeks. Rats were continued on respective experimental diets and sacrificed 8 weeks after the azoxymethane treatment. Colons were evaluated histopathologically for ACF. Administration of dietary 0.1% and 0.2% beta-ionone significantly suppressed total colonic ACF formation up to 34% to 38% (P<0.0002 to P<0.0009), respectively, when compared with control group. Importantly, rats fed beta-ionone showed >55% inhibition (P<0.0001) of foci containing four or more aberrant crypts. Results from in vitro and in vivo bioassay clearly suggest that beta-ionone could be further developed for prevention and treatment of colon cancer.

Anticancer effects of Chinese red yeast rice versus monacolin K alone on colon cancer cells

Chinese red yeast rice (RYR) is a food herb made by fermenting Monascus purpureus Went yeast with white rice. RYR contains a mixture of monacolins, one of which — monacolin K (MK) — is identical to lovastatin (LV). Epidemiological studies show that individuals taking statins have a reduced risk of colon cancer. In the present study, LV decreased cellular proliferation ( P<.001) and induced apoptosis ( P<.05) in HCT-116 and HT-29 human colon cancer cells. RYR inhibited both tumor cell growths ( P<.001) and enhanced apoptosis ( P<.05) in HCT-116 cells. Inhibition of proliferation was reversed by mevalonate (MV) in LV-treated cells, since LV is a 3-hydroxy-3-methyl-glutaryl CoA reductase (HMGCR) inhibitor. However, RYR with MV did not reverse the observed inhibition of growth. MK-free RYR did not reverse the observed LV-mediated inhibition of cancer cell growth. These observations suggest that other components in RYR, including other monacolins, pigments or the combined matrix effects of multiple constituents, may affect intracellular signaling pathways differently from purified crystallized LV in colon cancer cells. RYR was purified into two fractions: pigment-rich fraction of Chinese red yeast rice (PF-RYR) and monacolin-rich fraction of Chinese red yeast rice (MF-RYR). The effect of MF-RYR was similar to that of LV, while the effect of PF-RYR was similar to the effect of the whole RYR extract on the proliferation, apoptosis and mRNA level of HMGCR and sterol response element binding protein-2. These results suggest that the matrix effects of RYR beyond MK alone may be active in inhibiting colon cancer growth. RYR with or without MK may be a botanical approach to colon cancer chemoprevention worthy of further investigation.

Polyphenolic Coumpounds in Chemoprevention of Colon Cancer - Targets and Signaling Pathways

Colorectal cancer is one of the leading causes of premature death in people worldwide. Due to the fact that malignant conversion of normal colonic cells requires several steps and often proceeds over considerable time periods, primary prevention of this process should include several approaches, with optimization of nutrition and diet being among most important. During past decades, several groups of chemicals (both naturally occurring as well as synthetic) have been studied in terms of their potential chemopreventive role in colorectal cancer development. Naturally occurring plant polyphenols have recently come into scientific focus because of their presence in various popular natural products (wine grapes, teas, berries, peanuts) and, more importantly, due to their reported antiproliferative and cytostatic abilities in various in vitro and in vivo models. This review seeks to summarize the currently known targets and mechanisms whereby polyphenolic compounds interfere with colonic cancer cells while evaluating their chemopreventive potential in vivo.

Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo

Chemopreventive agents in colorectal cancer possess either antiproliferative or anti-inflammatory actions. Nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase-2 inhibitors have shown promise, but are compromised by side effects. Nitric oxide donor NSAIDs are organic nitrates conjugated via a labile linker to an NSAID, originally designed for use in pain relief, that have shown efficacy in colorectal cancer chemoprevention. The NO chimera, GT-094, is a novel nitrate containing an NSAID and disulfide pharmacophores, a lead compound for the design of agents specifically for colorectal cancer. GT-094 is the first nitrate reported to reduce aberrant crypt foci (by 45%) when administered after carcinogen in the standard azoxymethane rat model of colorectal cancer. Analysis of proximal and distal colon tissue from 8- and 28-week rat/azoxymethane studies showed that GT-094 treatment reduced colon crypt proliferation by 30% to 69%, reduced inducible NO synthase (iNOS) levels by 33% to 67%, reduced poly(ADP-ribose)polymerase-1 expression and cleavage 2- to 4-fold, and elevated levels of p27 in the distal colon 3-fold. Studies in cancer cell cultures recapitulated actions of GT-094: antiproliferative activity and transient G(2)-M phase cell cycle block were measured in Caco-2 cells; apoptotic activity was examined but not observed; anti-inflammatory activity was seen in the inhibition of up-regulation of iNOS and endogenous NO production in lipopolysaccharide (LPS)-induced RAW 264.7 cells. In summary, antiproliferative, anti-inflammatory, and cytoprotective activity observed in vivo and in vitro support GT-094 as a lead compound for the design of NO chimeras for colorectal cancer chemoprevention.

Curcumin for chemoprevention of colon cancer

The most practical approach to reduce the morbidity and mortality of cancer is to delay the process of carcinogenesis through the use of chemopreventive agents. This necessitates that safer compounds, especially those derived from natural sources must be critically examined for chemoprevention. A spice common to India and the surrounding regions, is turmeric, derived from the rhizome of Curcuma longa. Pre-clinical studies in a variety of cancer cell lines including breast, cervical, colon, gastric, hepatic, leukemia, oral epithelial, ovarian, pancreatic, and prostate have consistently shown that curcumin possesses anti-cancer activity in vitro and in pre-clinical animal models. The robust activity of curcumin in colorectal cancer has led to five phase I clinical trials being completed showing the safety and tolerability of curcumin in colorectal cancer patients. To date clinical trials have not identified a maximum tolerated dose of curcumin in humans with clinical trials using doses up to 8000 mg per day. The success of these trials has led to the development of phase II trials that are currently enrolling patients. Overwhelming in vitro evidence and completed clinical trials suggests that curcumin may prove to be useful for the chemoprevention of colon cancer in humans. This review will focus on describing the pre-clinical and clinical evidence of curcumin as a chemopreventive compound in colorectal cancer.

Chemopreventive effects of lupulone, a hop β-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.