lignans and Colorectal-Neoplasms

Flaxseed and its bioactive components have been associated with a decreased risk of colorectal cancer incidence and progression. This review aims to summarize recent research regarding the role of flaxseed and each of its major dietary bioactive components in reducing colorectal cancer.. In both human and animal model experiments, flaxseed consumption had beneficial effects on colon physiology associated with reduction in colorectal cancer risk or occurrence. Considered separately, each of flaxseed's major bioactive components, including fiber, alpha-linolenic acid, lignans, and other phytochemicals, is also associated with decreased risk of colonic neoplasms and regulation of cell growth through several potential mechanisms. Collectively, experimental data suggests that consumption of flaxseed and/or its bioactive components may reduce colorectal cancer risk by a variety of mechanisms. Future studies should focus on the mechanisms by which whole flaxseed can prevent colorectal cancer.

Topics: alpha-Linolenic Acid; Animals; Cell Proliferation; Colorectal Neoplasms; Dietary Fiber; Flax; Humans; Lignans; Phytochemicals; Seeds

To summarize available evidence on the association between dietary flavonoid as well as lignan intake and cancer risk in observational studies.. A systematic search on electronic databases of all English language case-control and prospective studies published up to June 2016 was performed. Risk ratios (RRs) and 95% confidence intervals were calculated by random-effects model separately by study design. Heterogeneity and publication bias were tested. Out of the 143 studies included, meta-analyses of prospective studies showed isoflavones significantly associated with decreased risk of lung and stomach cancers and nearly significant breast and colorectal cancers; total flavonoids showed nonsignificant decreased risk of breast cancer. Meta-analyses of case-control studies showed: total and/or individual classes of flavonoids associated with upper aero-digestive tract, colorectal, breast, and lung cancers; isoflavones with ovarian, breast, and colorectal cancers, endometrial and lung cancers.. Most evidence reported in previous meta-analyses was driven by case-control studies. Overall results may be promising but are inconclusive. Further prospective cohorts assessing dietary polyphenol exposure and studies using other methods to evaluate exposure (i.e. markers of consumption, metabolism, excretion) are needed to confirm and determine consumption levels required to achieve health benefits.

Topics: Breast Neoplasms; Case-Control Studies; Colorectal Neoplasms; Diet; Female; Flavonoids; Humans; Lignans; Odds Ratio; Polyphenols; Prospective Studies; Risk Factors

Epidemiological studies suggest that soya consumption as a source of phyto-oestrogens and isoflavones may be associated with a reduced risk of colorectal cancer. However, findings have not yet been synthesised for all groups of phyto-oestrogens. A meta-analysis was conducted to quantify the association between phyto-oestrogens and colorectal cancer risk. Relevant observational studies published up to June 2016 were identified by searching MEDLINE, EMBASE and Cochrane Library databases. Study-specific relative risks (RR) were pooled in both categorical and dose-response meta-analyses. Out of seventeen identified studies, sixteen were included in the meta-analysis. Comparing the highest with the lowest intake category, inverse associations for phyto-oestrogens overall and by subgroup were observed but were statistically significant in case-controls studies and not in cohort studies. The pooled RR in case-control studies were 0·76 (95 % CI 0·69, 0·84), 0·77 (95 % CI 0·69, 0·85) and 0·70 (95 % CI 0·56, 0·89) for phyto-oestrogens, isoflavones and lignans, respectively, whereas the corresponding pooled RR were 0·95 (95 % CI 0·85, 1·06), 0·94 (95 % CI 0·84, 1·05) and 1·00 (95 % CI 0·64, 1·57) in cohort studies. Dose-response analysis yielded an 8 % reduced risk of colorectal neoplasms for every 20 mg/d increase in isoflavones intake in Asians (pooled RR 0·92; 95 % CI 0·86, 0·97). A non-linear inverse association with colorectal cancer risk was found for lignans intake, but no association for circulating enterolactone concentrations was observed. Thus, study heterogeneity precludes a rigorous conclusion regarding an effect of high exposure to isoflavones on risk of colorectal cancer. Current evidence for an association with lignans exposure is limited. Further prospective studies, particularly evaluating lignans, are warranted to clarify the association between different phyto-oestrogens and colorectal cancer risk.

Topics: Adenoma; Animals; Colorectal Neoplasms; Diet, Healthy; Evidence-Based Medicine; Female; Functional Food; Humans; Incidence; Isoflavones; Lignans; Male; Observational Studies as Topic; Phytoestrogens; Reproducibility of Results; Risk; Sex Factors; Soy Foods

Phytoestrogens are polyphenolic secondary plant metabolites that have structural and functional similarities to 17beta-oestradiol and have been associated with a protective effect against hormone-related cancers. Most foods in the UK only contain small amounts of phytoestrogens (median content 21 microg/100 g) and the highest content is found in soya and soya-containing foods. The highest phytoestrogen content in commonly consumed foods is found in breads (average content 450 microg/100 g), the main source of isoflavones in the UK diet. The phytoestrogen consumption in cases and controls was considerably lower than in Asian countries. No significant associations between phytoestrogen intake and breast cancer risk in a nested case-control study in EPIC Norfolk were found. Conversely, colorectal cancer risk was inversely associated with enterolignan intake in women but not in men. Prostate cancer risk was positively associated with enterolignan intake, however this association became non-significant when adjusting for dairy intake, suggesting that enterolignans can act as a surrogate marker for dairy or calcium intake.

Topics: Aged; Animals; Breast Neoplasms; Case-Control Studies; Colorectal Neoplasms; Female; Food Analysis; Humans; Isoflavones; Lignans; Male; Middle Aged; Phytoestrogens; Prostatic Neoplasms; Risk Factors; United Kingdom

This review focuses on the possible role in human health of the consumption of lignan-rich foods. Most of the plant lignans in human foods are converted by the intestinal microflora in the upper part of the large bowel to enterolactone and enterodiol, called mammalian or enterolignans. The protective role of these compounds, particularly in chronic Western diseases, is discussed. Evidence suggests that fiber- and lignan-rich whole-grain cereals, beans, berries, nuts, and various seeds are the main protective foods. Many factors, in addition to diet, such as intestinal microflora, smoking, antibiotics, and obesity affect circulating lignan levels in the body. Lignan-rich diets may be beneficial, particularly if consumed for life. Experimental evidence in animals has shown clear anticarcinogenic effects of flaxseed or pure lignans in many types of cancer. Many epidemiological results are controversial, partly because the determinants of plasma enterolactone are very different in different countries. The source of the lignans seems to play a role because other factors in the food obviously participate in the protective effects. The results are promising, but much work is still needed in this area of medicine.

Topics: 4-Butyrolactone; Animals; Cardiovascular Diseases; Colorectal Neoplasms; Dietary Fiber; Edible Grain; Endometrial Neoplasms; Feeding Behavior; Female; Health Status; Humans; Isoflavones; Lignans; Male; Phytoestrogens; Plants, Edible; Prostatic Neoplasms; Seeds; Vegetables

Lignans and proanthocyanidins are plant polyphenols that have shown protective properties against colorectal neoplasms in some human studies. Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to prospectively evaluate the association between lignan and proanthocyanidin intake, estimated from databases linked to a food frequency questionnaire, and adenoma recurrence in 1,859 participants of the Polyp Prevention Trial. Overall, individual or total lignans or proanthocyanidins were not associated with colorectal adenoma recurrence. However, in sex-specific analyses, total lignan intake was positively associated with any adenoma recurrence in women (highest vs. lowest lignan intake quartile OR = 2.07, 95% CI: 1.22-3.52, p trend = 0.004) but not in men (p interaction = 0.04). To conclude, dietary lignan and proanthocyanidin consumption were not generally related to colorectal adenoma recurrence; however, high lignan intake may increase the risk of adenoma recurrence in women.

Topics: Adenoma; Aged; Colonic Polyps; Colorectal Neoplasms; Diet; Female; Humans; Lignans; Logistic Models; Male; Middle Aged; Neoplasm Recurrence, Local; Odds Ratio; Proanthocyanidins; Prospective Studies; Surveys and Questionnaires

Colorectal cancer (CRC) metastasis is a complicated process that not only involves tumor cells but also the effects of M2 type tumor-associated macrophages, a key component of the tumor microenvironment (TME), act a crucial role in cancer metastasis. Macelignan, an orally active lignan isolated from Myristica fragrans, possesses various beneficial biological activities, including anti-cancer effects, but its effect on macrophage polarization in the TME remains unknown.. To evaluate the inhibitory potency and prospective mechanism of macelignan on M2 polarization of macrophages and CRC metastasis.. The polarization and specific mechanism of M1 and M2 macrophage regulated by macelignan were determined by western blot, flow cytometry, immunofluorescence and network pharmacology. In vitro and in vivo function assays were performed to investigate the roles of macelignan in CRC metastasis.. Macelignan efficiently inhibited IL-4/13-induced polarization of M2 macrophages by suppressing the PI3K/AKT pathway in a reactive oxygen species (ROS)-dependent manner. The proportion of CD206. Macelignan suppressed macrophage M2 polarization via ROS-mediated PI3K/AKT signaling pathway, thus preventing IL-1β/NF-κB-dependent CRC metastasis. In the present study, we reveal a previously unrecognized mechanism of macelignan in the prevention of CRC metastasis and demonstrate its effectively and safely therapeutic potential in CRC treatment.

Topics: Colorectal Neoplasms; Humans; Lignans; Macrophages; NF-kappa B; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Tumor Microenvironment

Colorectal cancer (CRC), especially metastatic (mCRC) form, becomes a major reason behind cancer morbidity worldwide, whereas the treatment strategy is not optimum. Several novel targets are under investigation for mCRC including the autophagy pathway. Natural compounds including dietary lignans are sparsely reported as autophagy modulators. Nonetheless, the interaction between dietary lignans and core autophagy complexes are yet to be characterised. We aimed to describe the interaction between the dietary lignans from flaxseed (Linum usitatissimum) and sesame seeds (Sesamum indicum) along with the enterolignans (enterodiol and enterolactone) and the UNC-51-like kinase 1 and 2 (ULK1/2), important kinases required for the autophagy. A range of in-silico technologies viz. molecular docking, drug likeness, and ADME/T was employed to select the best fit modulator and/or inhibitor of the target kinases from the list of selected lignans. Drug likeness and ADME/T studied further selected the best-suited lignans as potential autophagy inhibitor. Molecular dynamic simulation (MDS) analyses were used to validate the molecular docking results. Binding free energies of the protein-ligand interactions by MM-PBSA method further confirmed best-selected lignans as ULK1 and/or ULK2 inhibitor. In conclusion, three dietary lignans pinoresinol, medioresinol, and lariciresinol successfully identified as dual ULK1/2 inhibitor/modifier, whereas enterodiol emerged as a selective ULK2 inhibitor/modifier.

Topics: Autophagy; Autophagy-Related Protein-1 Homolog; Colorectal Neoplasms; Humans; Lignans; Molecular Docking Simulation

In vitro cytotoxicity-guided isolation based on a MTT assay was conducted for Penthorum chinense Pursh. (Penthoraceae). In the active components (EtOAc extract of P. chinense), eight undescribed neolignans, penthoneolignans A-H (1-8), and two known analogs (9 and 10) were obtained and identified. Their absolute configurations were determined by experimental and computational comparison of electronic circular dichroism spectra analysis. The MTT experiment results of the obtained neolignans on HT29 and LoVo cells indicated previously undescribed neolignans, penthoneolignans A (1) and F (6), showed better cytotoxicity than the positive drug 5-fluorouracil. Then, functional technologies such as the 5-ethyny1-2'-deoxyridine, wound healing, Transwell, and Western blot assays indicated that they could significantly inhibit the proliferation of HT29 and Lovo cells, promote apoptosis by up-regulating Bax, and down-regulating B-cell CLL/lymphoma 2 and poly ADP-ribose polymerase. Furthermore, a Western blot assay combining the Dsh homolog 2 agonist IWP-L6 and the β-catenin agonist MG132 suggested their mechanism of action was closely related to the inhibition of the Wnt/β-catenin signaling pathway. In conclusion, previously undescribed neolignans, penthoneolignans A (1) and F (6), may intervene in the development and progression of colorectal cancer by inhibiting the Wnt/β-catenin signaling pathway and have the potential to be drug candidates.

Topics: Apoptosis; Circular Dichroism; Colorectal Neoplasms; Humans; Lignans; Wnt Signaling Pathway

Nanomedicine, constructed from therapeutics, presents an advantage in drug delivery for cancer therapies. However, nanocarrier-based treatment systems have problems such as interbatch variability, multicomponent complexity, poor drug delivery, and carrier-related toxicity. To solve these issues, the natural molecule honokiol (HK), an anticancer agent in a phase I clinical trial (CTR20170822), was used to form a self-assembly nanoparticle (SA) through hydrogen bonding and hydrophobicity. The preparation of SA needs no molecular precursors or excipients in aqueous solution, and 100% drug-loaded SA exhibited superior tumor-targeting ability due to the enhanced permeability and retention (EPR) effect. Moreover, SA significantly enhanced the antitumor immunity relative to free HK, and the mechanism has notable selectivity to the p53 pathway. Furthermore, SA exhibited excellent physiological stability and inappreciable toxicity. Taken together, this supramolecular self-assembly strategy provides a safe and "molecular economy" model for rational design of clinical therapies and is expected to promote targeted therapy of HK, especially in colorectal cancer patients with obvious p53 status.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biocompatible Materials; Biphenyl Compounds; Colorectal Neoplasms; Female; Humans; Immunotherapy; Lignans; Macromolecular Substances; Materials Testing; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Neoplasms, Experimental; Small Molecule Libraries; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Topics: Animals; Cell Line, Tumor; Colorectal Neoplasms; Dioxoles; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Lignans; Mice; Mice, Nude; Neovascularization, Pathologic; NF-kappa B; Signal Transduction; Vascular Endothelial Growth Factor A

Sesamin, a lignan compound, exhibits a variety of biological activities and possesses potent anticancer properties on some human cancers. However, its effect on human colorectal cancer (CRC) remains to be elucidated. To investigate the effects of sesamin on CRC cells and further to explore the mechanisms, cell viability, cell cycle and apoptosis assays were performed in this study. We found that sesamin had a selective antiproliferation of CRC cell line HCT116 in a dose- and time-dependent manner, but no obvious effect on human normal colorectal mucosa epithelial cell FHC. Further study showed that sesamin-induced cell cycle arrest and decreased the expression of Cyclin D1 significantly and dose-dependently in HCT116 cells. Moreover, sesamin dose-dependently triggered apoptosis of HCT116 but not FHC, and promoted the expression levels of proapoptotic biomarkers Bax, cleaved caspase-3 and cleaved PARP-1 and inhibited the expression of antiapoptotic biomarker Bcl-2. Western blot analysis was used to reveal the possible signaling pathways, and we found that sesamin upregulated the phosphorylation expression levels of C-Jun N-terminal kinase (JNK) and p38 except ERK1/2 in a dose-dependent way in both HCT116 and another CRC cell line SW480. Moreover, we found that the apoptosis effect induced by sesamin was partially eliminated by inhibiting JNK or p38 activation. Finally, we showed that sesamin effectively reduced the growth of xenograft tumors derived from cell lines with limited toxicity. Taken together, the potential ability of sesamin to induce cell cycle arrest and apoptosis was shown to be via the p38 and JNK mitogen-activated protein kinase signaling pathways, which may be one of the mechanisms of the anticancer activity of this low-toxic agent.

Topics: Animals; Antioxidants; Apoptosis; Cell Cycle; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Cyclin D1; Dioxoles; Dose-Response Relationship, Drug; Humans; JNK Mitogen-Activated Protein Kinases; Lignans; Mice; Mice, Inbred BALB C; p38 Mitogen-Activated Protein Kinases; Signal Transduction; Time Factors; Up-Regulation

Ca. Patch-clamp techniques were performed to study the effect of honokiol on Ca. Honokiol blocked Ano1 currents in Ano1-overexpressing HEK293 cells and SW620 cells. Honokiol more potently inhibited Ano1 currents than Ano2 currents. Three amino acids (R429, K430 and N435) were critical for honokiol-induced Ano1 inhibition. The R429A/K430L/N435G mutation reduced the sensitivity of Ano1 to honokiol. Honokiol inhibited SW620 cell proliferation, and this effect was reduced by Ano1-shRNAs. Furthermore, Ano1 overexpression promoted proliferation in NCM460 cells with low Ano1 endogenous expression and resulted in an increased sensitivity to honokiol. Overexpression of the R429A/K430L/N435G mutation reduced WT Ano1-induced increase in the sensitivity of NCM460 cells to honokiol.. We identified a new anticancer mechanism of honokiol, through the inhibition of cell proliferation, by targeting Ano1 Ca

Topics: Anoctamin-1; Biphenyl Compounds; Calcium; Cell Proliferation; Chloride Channels; Colorectal Neoplasms; HEK293 Cells; Humans; Lignans

Heat shock factor 1 (HSF1) is a powerful multifaceted oncogenic modifier that plays a role in maintaining the protein balance of cancer cells under various stresses. In recent studies, there have been reports of increased expression of HSF1 in colorectal cancer (CRC) cells, and the depletion of the HSF1 gene knockdown has inhibited colon cancer growth both in vivo and in vitro. Therefore, HSF1 is a promising target for colon cancer treatment and chemoprevention. In the present study, we found that Schizandrin A (Sch A) significantly inhibited the growth of CRC cell lines by inducing cell cycle arrest, apoptosis and death. Through HSE luciferase reporter assay and quantitative PCR (qPCR), we identified Sch A as a novel HSF1 inhibitor. In addition, Sch A could effectively inhibit the induction of HSF1 target proteins such as heat-shock protein (HSP) 70 (HSP70) and HSP27, whether in heat shock or normal temperature culture. In the Surface Plasmon Resonance (SPR) experiment, Sch A showed moderate affinity with HSF1, further confirming that Sch A might be a direct HSF1 inhibitor. The molecular docking and molecular dynamic simulation results of HSF1/Sch A suggested that Sch A formed key hydrogen bond and hydrophobic interactions with HSF1, which may contribute to its potent HSF1 inhibition. These findings provide clues for the design of novel HSF1 inhibitors and drug candidates for colon cancer treatment.

Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; China; Colonic Neoplasms; Colorectal Neoplasms; Cyclooctanes; DNA-Binding Proteins; Heat Shock Transcription Factors; HSP27 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Lignans; Molecular Docking Simulation; Polycyclic Compounds; Transcription Factors

Topics: Animals; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Disease Progression; Humans; Lignans; Male; Mice, Inbred BALB C; Mitochondria; Neoplasm Invasiveness; NF-kappa B; Phosphorylation; Protein Kinase C-delta; Protein Kinase Inhibitors; Receptors, Death Domain; Signal Transduction

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Here, we investigated the molecular mechanisms that underpin the anticancer effects of cleistanthin A (CA) in two CRC cell lines, HCT 116, and SW480. At 48 h, CA exhibited apoptotic cytotoxic effects in both CRC cell lines, concomitant with reduction of an anti-apoptotic protein, survivin. Mechanistically, CA treatment significantly reduced the expression levels of β-catenin and active-β-catenin in a dose-dependent manner in both CRC cell lines. Moreover, CA suppressed the Wnt/β-catenin signaling pathway by decreasing β-catenin-mediated transcriptional activity and expression of β-catenin target genes, AXIN2, CCND1, and survivin. Furthermore, CA also inhibited transcriptional activity in cells overexpressing a constitutively active β-catenin S33Y, indicating a GSK-3β-independent mechanism underlying the observed CA effects on CRC cells. Although cytotoxic activity was not observed with CA treatment at 24 h, cell migration and invasion were significantly reduced. In addition, CA suppressed V-type ATPase activity and focal adhesion kinase (FAK) phosphorylation. Collectively, our study reveals that CA has time-dependent effects on CRC cell phenotypes. First, short-term CA treatment inhibited CRC cell migration and invasion partly through the suppression of V-type ATPase activity. This suppression resulted in reduced FAK activation. Second, longer-term CA treatment decreased cell viability which correlated with the suppression of Wnt/β-catenin signaling induced transcriptional activity. Altogether, our data suggest that CA has the potential to develop as an effective and novel therapeutic drug for CRC patients.

Topics: Apoptosis; Cell Movement; Colorectal Neoplasms; Dose-Response Relationship, Drug; Glycosides; HCT116 Cells; HEK293 Cells; Humans; Lignans; Neoplasm Invasiveness; Toxins, Biological; Wnt Signaling Pathway

Arctigenin is the active content of arctium lappa that present anti-cancer abilities in various carcinomas. However, its role and underlying mechanism in drug-resistant colorectal cancer cells has not been addressed. The present study used SW480 and SW620 to established cisplatin-resistant colorectal cancer cell lines, and explored the impact of arctigenin on these cells. Arctigenin at 100 μM significantly inhibited cell proliferation of cisplatin treated R-SW480 and R-SW620 cells as compared with cells treated with cisplatin alone. Arctigenin elevates cell apoptosis, up-regulated pro-apoptotic protein cleaved-caspase-3 and caspase-9 expression level in cisplatin treated R-SW480 and R-SW620 cells. Additionally, arctigenin triggered autophagy and promoted LC3-Ⅱ and p65 expression, while inhibited LC3-Ⅰexpression. Arctigenin impeded the IC

Topics: Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B; Autophagy; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Proliferation; Cisplatin; Colorectal Neoplasms; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Furans; Humans; Inhibitory Concentration 50; Lignans; Oxaliplatin; Paclitaxel; Up-Regulation

The association between lifestyle and survival after colorectal cancer has received limited attention. The female sex hormone, oestrogen, has been associated with lower colorectal cancer risk and mortality after colorectal cancer. Phyto-oestrogens are plant compounds with structure similar to oestrogen, and the main sources in Western populations are plant lignans. We investigated the association between the main lignan metabolite, enterolactone and survival after colorectal cancer among participants in the Danish Diet, Cancer and Health cohort. Prediagnosis plasma samples and lifestyle data, and clinical data from time of diagnosis from 416 women and 537 men diagnosed with colorectal cancer were used. Enterolactone was measured in plasma using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Participants were followed from date of diagnosis until death or end of follow-up. During this time, 210 women and 325 men died (170 women and 215 men died due to colorectal cancer). The Cox proportional hazards model was used to estimate hazard ratios (HR) and 95 % CI. Enterolactone concentrations were associated with lower colorectal cancer-specific mortality among women (HRper doubling: 0·88, 95 % CI 0·80, 0·97, P=0·0123). For men, on the contrary, enterolactone concentrations were associated with higher colorectal cancer-specific mortality (HRper doubling: 1·10, 95 % CI 1·01, 1·21, P=0·0379). The use of antibiotics affects enterolactone production, and the associations between higher enterolactone and lower colorectal cancer-specific mortality were more pronounced among women who did not use antibiotics (analysis on a subset). Our results suggest that enterolactone is associated with lower risk of mortality among women, but the opposite association was found among men.

Topics: 4-Butyrolactone; Aged; Cohort Studies; Colorectal Neoplasms; Denmark; Diet; Female; Humans; Incidence; Lignans; Male; Middle Aged; Survival Analysis

Enterodiol (END) is transformed by human intestinal bacteria from lignans contained in various whole-grain cereals, nuts, legumes, flaxseed, and vegetables. It is known to have several physiological effects, but its effects on mitogen-activated protein kinase (MAPK) signaling and apoptosis in colorectal cancer (CRC) cells have not yet been elucidated. We therefore investigated the effects of END on apoptosis in CRC cells and whether these effects are mediated via MAPK signaling.. Cell proliferation was decreased by END treatment in a time-dependent manner. In particular, END treatment resulted in an apoptosis rate of up to 40% in CT26 cells but showed no cytotoxicity toward RAW264.7 macrophages. Treatment with END also suppressed the migration of CRC cells in a concentration-dependent manner. The phosphorylation of extracellular signal-regulated kinase (ERK), jun N-terminal kinase (JNK), and p38 was down-regulated with END treatment. Furthermore, END decreased the expression levels of anti-apoptotic proteins in CRC cells.. Enterodiol inhibited the growth of CRC cells by controlling the MAPK signaling pathway involved in proliferation and apoptosis. These results demonstrate that END has an apoptotic effect in CRC cells. © 2018 Society of Chemical Industry.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Extracellular Signal-Regulated MAP Kinases; Humans; Lignans; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Signal Transduction

To evaluate the relationship between phytoestrogen and colon cancer risk, we quantified plasma isoflavones (Genistein and Daidzein) and lignan (enterolactone) in a Korean nested case-control study and conducted replication study in a Vietnamese case-control study.. Study populations of 101 cases and 391 controls were selected from the Korean Multicenter Cancer Cohort which was constructed from 1993 to 2004. For replication study, Vietnamese hospital-based case-control subjects of 222 cases and 206 controls were selected from 2003 to 2007. The concentrations of plasma genistein, daidzein, and enterolactone were quantified by liquid chromatography-mass spectrometry. Logistic regression models were used to compute odds ratios (ORs) and 95% confidence intervals (CIs), and meta-analysis was conducted to estimate combined ORs (CORs) and 95% Cis of Korean and Vietnamese population in 2014.. Genistein showed a continual decrease in colorectal cancer risk according to level up of the concentration categories in Korean and Vietnamese population (P for trend = 0.032, and 0.001, respectively) and a significantly decreased risk was found at the highest concentration of genistein and daidzein (for the highest category compared to the lowest: COR (95% CI) = 0.46 (0.30-0.69), and COR (95% CI) = 0.54 (0.36-0.82)). When the study population was stratified, the beneficial relationship of genistein with colorectal cancer was observed regardless of sex and anatomical subtype. However, enterolacton level was not associated with colorectal cancer risk.. High plasma levels of isoflavones had relationship with a decreased risk of colorectal cancer, regardless of different ethnic background.

Topics: 4-Butyrolactone; Adult; Aged; Asian People; Case-Control Studies; Colorectal Neoplasms; Female; Genistein; Humans; Isoflavones; Lignans; Male; Middle Aged; Phytoestrogens; Republic of Korea; Risk Factors; Vietnam

Magnolin is a multi-bioactive natural compound that possesses underlying anti-cancer properties. However, the mechanisms underlying remain to be elucidated. Here, we report the role of magnolin in suppressing human colorectal cancer (CRC) cells via activating autophagy and cell cycle arrest in vitro and in vivo. Pre-treatment of cells with specific autophagy inhibitor (3-methyladenine) or knockdown of endogenous LC-3B by siRNA significantly abrogates magnolin-induced cell cycle arrest. Molecular validation mechanistically shows that magnolin-induced autophagy and cell cycle arrest in CRC cells is correlated with decreased transcriptional levels of leukemia inhibitory factor (LIF), and we further find that inhibition of LIF decreases phosphorylation level of Stat3 and represses transcriptional expression of Mcl-1. Furthermore, magnolin-induced autophagy and cell cycle arrest suppress the growth of xenograft colorectal tumors without apparent toxicity. Finally, we evaluate the clinical correlation of LIF/Stat3/Mcl-1 in CRC patient tissues. As expected, LIF, p-Stat3, and Mcl-1 levels are high in CRC tissue but are scarcely found in normal colon tissue. High positive expressions of LIF or Mcl-1 are associated with poor prognosis. Doubly positive cases have shown the worst outcome. Taken together, our results have clarified a novel molecular mechanism whereby magnolin induces autophagy and cell cycle arrest through LIF/Stat3/Mcl-1 pathway in CRCs. Our results also have revealed that magnolin has a promising therapeutic potential in CRCs.

Topics: Animals; Autophagy; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Humans; Leukemia Inhibitory Factor; Lignans; Mice, Inbred BALB C; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; Prognosis; Signal Transduction; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Arctigenin (ARC) has been shown to have an anti-cancer effect in various cell types and tissues. However, there have been no studies concerning metastatic colorectal cancer (CRC). In this study, we investigated the anti-metastatic properties of ARC on colorectal metastasis and present a potential candidate drug. ARC induced cell cycle arrest and apoptosis in CT26 cells through the intrinsic apoptotic pathway via MAPKs signaling. In several metastatic phenotypes, ARC controlled epithelial-mesenchymal transition (EMT) through increasing the expression of epithelial marker E-cadherin and decreasing the expressions of mesenchymal markers; N-cadherin, vimentin, β-catenin, and Snail. Moreover, ARC inhibited migration and invasion through reducing of matrix metalloproteinase-2 (MMP-2) and MMP-9 expressions. In an experimental metastasis model, ARC significantly inhibited lung metastasis of CT26 cells. Taken together, our study demonstrates the inhibitory effects of ARC on colorectal metastasis.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Female; Furans; Lignans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Metastasis

Our previous reports showed that justicidin A (JA), a novel and pure arylnaphthalide lignan isolated from Justicia procumbens, induces apoptosis of human colorectal cancer cells and hepatocellular carcinoma cells, leading to the suppression of both tumor cell growth in NOD-SCID mice. Here, we reveal that JA induces autophagy in human colorectal cancer HT-29 cells by conversion of autophagic marker LC3-I to LC3-II. Furthermore, LC3 puncta and autophagic vesicle formation, and SQSTM1/p62 suppression were observed. Administration of autophagy inhibitor (bafilomycin A1 and chloroquine) and transfection of a tandem fluorescent-tagged LC3 (mRFP-GFP) reporter plasmid (ptfLC3) demonstrated that JA induces autophagy flux in HT-29 cells. Expression of LC3, SQSTM1, Beclin 1, and nuclear DNA double-strand breaks (representing apoptosis) were also detected in the tumor tissue of HT-29 cells transplanted into NOD-SCID mice orally administrated with JA. In addition, the expression of autophagy signaling pathway-related molecules p-PDK1, p-mTOR, p-p70S6k/p-RPS6KB2 was decreased, whereas that of class III PI3K, Beclin 1, Atg5-Atg12, and mitochondrial BNIP3 was increased in response to JA. Pre-treatment of the cells with class III PI3K inhibitor 3-methyladenine or Atg5 shRNA attenuated JA-induced LC3-II expression and LC3 puncta formation, indicating the involvement of class III PI3K and Atg5. A novel mechanism was demonstrated in the anticancer compound JA; pre-treatment with 3-methyladenine or Atg5 shRNA blocked JA-induced suppression in cell growth and colony formation, respectively, via inhibition of apoptosis. In contrast, administration of apoptosis inhibitor Z-VAD did not affect JA-induced autophagy. Our data suggest the chemotherapeutic potential of JA for treatment of human colorectal cancer.

Topics: Adenine; Animals; Apoptosis; Autophagy; Autophagy-Related Protein 5; Colorectal Neoplasms; Dioxolanes; HT29 Cells; Humans; Lignans; Mice; Mice, SCID; Microtubule-Associated Proteins; Phosphatidylinositol 3-Kinases; RNA, Small Interfering; Signal Transduction

Flavonoids and lignans are polyphenol classes with anticarcinogenic activities against colorectal cancer (CRC). However, very limited epidemiological evidence exists on their effects on CRC prognosis. This study aimed to evaluate the association between flavonoid and lignan intakes with the risk of CRC recurrence and overall survival in CRC patients. The study followed incident histologically confirmed CRC cases in Barcelona (Spain). Validated dietary questionnaires and lifestyle information were collected at recruitment. An ad hoc food composition database on flavonoids and lignans was compiled by using data from the US Department of Agriculture and Phenol-Explorer databases. Adjusted hazards ratios (HR) and 95% confidence intervals (CIs) were estimated using multivariable Cox models. After 8.6 years of mean follow-up, 133 of 409 (32.5%) participants died and 77 of 319 (24.1%) had a CRC recurrence. Total flavonoids were associated neither with CRC recurrence (HR comparing extreme tertiles 1.13, 95% CI 0.64-2.02; P-trend 0.67) nor with overall survival (HR(T3vsT1) 1.06, 95% CI 0.69-1.65; P-trend 0.78) in the multivariable models. No associations were also observed with either total lignans or any flavonoid subclass intake. In conclusion, the results of the current study do not support a role of flavonoid and lignan intake in the CRC prognosis.

Topics: Aged; Colorectal Neoplasms; Diet; Female; Flavonoids; Follow-Up Studies; Humans; Lignans; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Proportional Hazards Models; Risk Factors; Spain

Honokiol is a small biphenolic compound, which exerts antitumor activities; however, the precise mechanism of honokiol-induced apoptosis in the human colorectal cancer cells remains unclear. Here, we show that survivin and p53 display the opposite role on the regulation of honokiol-induced apoptosis in the human colorectal cancer cells. Honokiol induced the cell death and apoptosis in various colorectal cancer cell lines. Moreover, honokiol elicited the extrinsic death receptor pathway of DR5 and caspase 8 and the intrinsic pathway of caspase 9. The common intrinsic and extrinsic downstream targets of activated caspase 3 and PARP protein cleavage were induced by honokiol. Interestingly, honokiol reduced anti-apoptotic survivin protein and gene expression. Transfection with a green fluorescent protein (GFP)-survivin-expressed vector increased the colorectal cancer cell viability and resisted the honokiol-induced apoptosis. Meantime, honokiol increased total p53 and the phosphorylated p53 proteins at Ser15 and Ser46. The p53-wild type colorectal cancer cells were exhibited greater cytotoxicity, apoptosis and survivin reduction than the p53-null cancer cells after treatment with honokiol. Together, these findings demonstrate that the existence of survivin and p53 can modulate the honokiol-induced apoptosis in the human colorectal cancer cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Drug Resistance, Neoplasm; HCT116 Cells; Humans; Inhibitor of Apoptosis Proteins; Lignans; Signal Transduction; Survivin; Tumor Suppressor Protein p53

Carya cathayensis is a fruit-bearing plant that belongs to the Juglandaceae family and is widely distributed throughout the world. It possesses various important biological activities. We have previously isolated an antitumor compound from the shell of C. cathayensis fruits and named it E2S ((E)-3-[(2S,3R)-2,3-dihydro-2-(4'-hydroxy-3'-methoxyphenyl)-3-hydroxymethyl-7-methoxy-1-benzo[b]furan-5-yl]-2-propenal). In this study, we investigated the antitumor activity of E2S against various human colorectal cancer cell lines (HCT116, HT29, SW480, LoVo). The results showed that E2S could significantly inhibit the growth of cancer cells in a dose-dependent manner, as well as disrupt the progression of the cell cycle. Mechanistic study revealed that E2S could decrease the protein levels of β-catenin and its downstream targets (such as c-myc, a key transcriptional target of β-catenin) in the cells. In addition, it also significantly suppressed β-catenin/TCF transcriptional activity. Taken together, the results suggested that E2S might partially exert an antiproliferative effect on human colorectal cancer cells by targeting β-catenin signaling, a finding that might potentially translate into a chemotherapeutic strategy for the treatment of cancer. It might also have implications for cancer prevention strategies.

Topics: Antineoplastic Agents, Phytogenic; beta Catenin; Carya; Cell Cycle; Colorectal Neoplasms; Fruit; HCT116 Cells; HT29 Cells; Humans; Lignans; Phytotherapy; Plant Extracts; Signal Transduction; Transcription, Genetic

Flavonoid-rich foods, such as fruits, vegetables, and tea, may have a protective effect upon colorectal cancer. However, current epidemiological evidence for a protective effect of flavonoid intake upon colorectal cancer is promising but not conclusive.. To examine the relation between dietary flavonoid and lignan intakes and the risk of colorectal cancer within a Spanish population.. Data from the Bellvitge Colorectal Cancer Study, a case-control study (424 cases with incident colorectal cancer and 401 hospital-based controls), were used. A reproducible and validated food frequency questionnaire was administered in personal interviews. An ad hoc food composition database on flavonoids and lignans was compiled, mainly using data from the US Department of Agriculture and Phenol-Explorer databases. Adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated using unconditional logistic regression models.. An inverse association was found between intake of total flavonoids (OR, 0.59; 95 % CI, 0.35-0.99 for the highest vs. the lowest quartile; p for trend = 0.04), lignans (OR, 0.59; 95 % CI, 0.34-0.99; p for trend = 0.03), and some individual flavonoid subgroups (flavones, proanthocyanidins) and the risk of colorectal cancer. Separate analyses by cancer site showed similar results.. Intake of total dietary flavonoids (particularly certain flavonoid subgroups) and lignans was inversely associated with colorectal cancer risk in a Spanish population.

Topics: Aged; Case-Control Studies; Colorectal Neoplasms; Diet; Female; Flavonoids; Fruit; Humans; Incidence; Lignans; Male; Spain; Vegetables

Abnormal activation of the canonical Wnt/β-catenin pathway and up-regulation of the β-catenin/T-cell factor (TCF) response to transcriptional signaling play a critical role early in colorectal carcinogenesis. Therefore, Wnt/β-catenin signaling is considered an attractive target for cancer chemotherapeutic or chemopreventive agents. Small molecules derived from the natural products were used in our cell-based reporter gene assay to identify potential inhibitors of Wnt/β-catenin signaling. Magnolol, a neolignan from the cortex of Magnolia obovata, was identified as a promising candidate because it effectively inhibited β-catenin/TCF reporter gene (TOPflash) activity. Magnolol also suppressed Wnt3a-induced β-catenin translocation and subsequent target gene expression in human embryonic kidney 293 cells. To further investigate the precise mechanisms of action in the regulation of Wnt/β-catenin signaling by magnolol, we performed Western blot analysis, real-time reverse transcriptase-polymerase chain reactions, and an electrophoretic mobility shift assay in human colon cancer cells with aberrantly activated Wnt/β-catenin signaling. Magnolol inhibited the nuclear translocation of β-catenin and significantly suppressed the binding of β-catenin/TCF complexes onto their specific DNA-binding sites in the nucleus. These events led to the down-regulation of β-catenin/TCF-targeted downstream genes such as c-myc, matrix metalloproteinase-7, and urokinase-type plasminogen activator in SW480 and HCT116 human colon cancer cells. In addition, magnolol inhibited the invasion and motility of tumor cells and exhibited antitumor activity in a xenograft nude mouse model bearing HCT116 cells. These findings suggest that the growth inhibition of magnolol against human colon cancer cells can be partly attributed to the regulation of the Wnt/β-catenin signaling pathway.

Topics: Animals; Antineoplastic Agents, Phytogenic; beta Catenin; Biphenyl Compounds; Colorectal Neoplasms; Female; HCT116 Cells; HEK293 Cells; Humans; Lignans; Mice; Mice, Inbred BALB C; Mice, Nude; Signal Transduction; Wnt3A Protein; Xenograft Model Antitumor Assays

DNA mismatch repair is required for correcting any mismatches that are created during replication and recombination, and a defective mismatch repair system contributes to DNA damage-induced growth arrest. The colorectal cancer cell line HCT116 is known to have a mutation in the hMLH1 mismatch repair gene resulting in microsatellite instability and defective mismatch repair. Honokiol is a biphenolic compound that has been used in traditional Chinese medicine for treating various ailments including cancer. This study was designed to test the hypothesis that honokiol enhances the radiosensitivity of cancer cells with mismatch repair defect (HCT116) compared with those that are mismatch repair proficient (HCT116-CH3). We first determined that the combination of honokiol and γ-irradiation treatment resulted in dose-dependent inhibition of proliferation and colony formation in both cell lines. However, the effects were more pronounced in HCT116 cells. Similarly, the combination induced higher levels of apoptosis (caspase 3 activation, Bax to Bcl2 ratio) in the HCT116 cells compared with HCT116-CH3 cells. Cell cycle analyses revealed higher levels of dead cells in HCT116 cells. The combination treatment reduced expression of cyclin A1 and D1 and increased phosphorylated p53 in both cell lines, although there were significantly lower amounts of phosphorylated p53 in the HCT116-CH3 cells, suggesting that high levels of hMLH1 reduce radiosensitivity. These data demonstrate that honokiol is highly effective in radiosensitizing colorectal cancer cells, especially those with a mismatch repair defect.

Topics: Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; DNA Mismatch Repair; HCT116 Cells; Humans; Lignans; Radiation Tolerance; Radiation-Sensitizing Agents; Tumor Cells, Cultured

The characterization of phytoestrogen intake and cancer risk has been hindered by the absence of accurate dietary phytoestrogen values.. We examined the risk of breast, colorectal, and prostate cancers relative to phytoestrogen intake on the basis of a comprehensive database.. Demographic and anthropometric characteristics, a medical history, and 7-d records of diet were collected prospectively from participants (aged 40-79 y) in the European Prospective Investigation into Cancer and Nutrition-Norfolk (EPIC-Norfolk). Five hundred nine food items were analyzed by liquid chromatography-mass spectrometry/mass spectrometry, and (13)C(3)-labeled internal standards were analyzed for isoflavones (genistein, daidzein, glycitein, biochanin A, and formononetin), lignans (secoisolariciresinol and matairesinol), and enterolignans from gut microbial metabolism in animal food sources (equol and enterolactone). From the direct analysis, values for 10,708 foods were calculated. Odds ratios (ORs) for breast (244 cases, 941 controls), colorectal (221 cases, 886 controls), and prostate (204 cases, 812 controls) cancers were calculated relative to phytoestrogen intake.. Phytoestrogen intake was not associated with breast cancer among women or colorectal cancer among men. Among women, colorectal cancer risk was inversely associated with enterolactone (OR: 0.33; 95% CI: 0.14, 0.74) and total enterolignans (OR: 0.32; 95% CI: 0.13, 0.79), with a positive trend detected for secoisolariciresinol (OR: 1.60; 95% CI: 0.96, 2.69). A positive trend between enterolignan intake and prostate cancer risk (OR: 1.27; 95% CI: 0.97, 1.66) was attenuated after adjustment for dairy intake (OR: 1.19; 95% CI: 0.77, 1.82).. Dietary phytoestrogens may contribute to the risk of colorectal cancer among women and prostate cancer among men.

Topics: Adult; Aged; Breast Neoplasms; Case-Control Studies; Colorectal Neoplasms; Female; Gas Chromatography-Mass Spectrometry; Humans; Incidence; Isoflavones; Lignans; Logistic Models; Male; Middle Aged; Phytoestrogens; Prospective Studies; Prostatic Neoplasms; Risk Factors; Spectrometry, Mass, Electrospray Ionization; United Kingdom

Separate benzocyclooctadiene lignans were isolated from the berries of Schisandra chinensis in milligram quantities on analytical reverse phase (RP) HPLC by an automated repeat-injection method and shown to have anti-proliferative activity against human colorectal cancer cells. Structures of the compounds were determined by a combination of NMR and mass spectrometry. Stereospecific NMR assignments for gomisin-N and deoxyschisandrin, gave more complete and accurate data than previously reported, based on 600MHz 2D HSQC, DQF-COSY and HMBC data. Comparison of coupling constants and HMBC crosspeak intensities with calculated and X-ray crystal structures confirmed their stereochemistry and conformation. Analysis of structure-activity relationships revealed the importance of key structural determinants. The S-biphenyl configuration of gomisin N, the most active lignan, correlated with increased anti-proliferative activity, while the presence of a hydroxyl group at the C7 position reduced or abolished this activity. Increased activity was also observed when a methylenedioxy group was present between C12 and C13. The percent yield of the most active compounds relative to the starting plant materials was 0.0156% for deoxyschisandrin and 0.0173% for gomisin N. The results of these studies indicate that automated repeat-injection method of analytical HPLC may provide a superior alternative to the standard semi-preparative HPLC techniques for separation of complex mixtures.

Topics: Cell Survival; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Colorectal Neoplasms; Cyclooctanes; Fruit; Hexanes; HT29 Cells; Humans; K562 Cells; Lignans; Methylene Chloride; Nuclear Magnetic Resonance, Biomolecular; Plant Extracts; Schisandra; Structure-Activity Relationship

Enterolignans are biphenolic compounds that possess several biologic activities whereby they may influence carcinogenesis. The authors investigated the association between plasma enterolactone and enterodiol and colorectal cancer risk in a Dutch prospective study. Among more than 35,000 participants aged 20-59 years, 160 colorectal cancer cases were diagnosed after 7.5 years of follow-up (1987-2003). Cohort members who were frequency-matched to the cases on age, sex, and study center were selected as controls (n = 387). Plasma enterodiol and enterolactone were not associated with risk of colorectal cancer after adjustment for known colorectal cancer risk factors (highest quartile vs. lowest: for enterodiol, odds ratio = 1.11, 95% confidence interval: 0.56, 2.20 (p-trend = 0.75); for enterolactone, odds ratio = 1.70, 95% confidence interval: 0.88, 3.27 (p-trend = 0.15)). However, sex (p-interaction = 0.06) and body mass index (p-interaction < 0.01) modified the relation between plasma enterolactone and colorectal cancer risk; increased risks were observed among women and subjects with a high body mass index. The association between plasma enterodiol and colorectal cancer risk was modified by smoking status; risk was increased among current smokers (p-interaction < 0.01). These findings do not support the hypothesis that high plasma enterodiol or enterolactone concentrations are associated with reduced risk of colorectal cancer.

Topics: Adult; Biphenyl Compounds; Body Mass Index; Case-Control Studies; Colorectal Neoplasms; Female; Humans; Lignans; Male; Middle Aged; Netherlands; Prospective Studies; Risk Assessment; Risk Factors; Smoking

Enterolignans are phytoestrogenic compounds derived from the conversion of dietary lignans by the intestinal microflora that may be protective against cardiovascular diseases and cancer. To evaluate the use of enterolignans as biomarkers of dietary lignan intake, we studied the relation between plasma and dietary lignans. We determined the dietary intake of 4 lignans (secoisolariciresinol (SECO), matairesinol (MAT), pinoresinol, and lariciresinol) using the European Prospective Investigation into Cancer and Nutrition FFQ, and plasma enterodiol (END) and enterolactone (ENL) concentrations were determined by liquid chromatography-tandem mass spectrometry. The population consisted of 637 men and women, aged 19-75 y, participating in a case-control study on colorectal adenomas. Participants did not use antibiotics in the preceding calendar year. We found a modest association between lignan intake and plasma END (Spearman r = 0.09, P = 0.03) and ENL (Spearman r = 0.18, P <0.001). The correlation of total lignan intake with plasma enterolignans was slightly stronger than that of only SECO plus MAT. The plasma concentrations of both END and ENL were associated with intake of dietary fiber and vegetable protein but not with intake of other macronutrients. The relation between lignan intake and plasma END was modulated by age and previous use of antibiotics, whereas for ENL, it was modulated by weight, current smoking, and frequency of defecation. However, even when we included these nondietary factors in the regression models, the explained variance in plasma END and ENL remained low (2 and 13%, respectively).

Topics: 4-Butyrolactone; Adenomatous Polyps; Adult; Aged; Case-Control Studies; Colonoscopy; Colorectal Neoplasms; Diet; Female; Humans; Lignans; Male; Middle Aged; Phytoestrogens

Lignans are biphenolic compounds that occur in foods of plant origin such as whole grains, seeds, fruits and vegetables, and beverages, such as coffee and tea. Plant lignans are converted by intestinal bacteria into the enterolignans, enterodiol and enterolactone. Enterolignans possess several biological activities, whereby they may influence carcinogenesis. We studied the associations between plasma enterolignans and the risk of colorectal adenomas in a Dutch case-control study. Colorectal adenomas are considered to be precursors of colorectal cancer. Cases (n = 532) with at least one histologically confirmed colorectal adenoma and controls (n = 503) with no history of any type of adenoma were included. Plasma enterodiol and enterolactone concentrations were measured by liquid chromatography with tandem mass spectrometry. Associations were stronger for incident than for prevalent cases. When only incident cases (n = 262) were included, high compared to low plasma concentrations of enterodiol were associated with a reduction in colorectal adenoma risk after adjustment for confounding variables. Enterodiol odds ratios (95% confidence intervals) were 1.00, 0.69 (0.42-1.13), 0.60 (0.37-0.99), and 0.53 (0.32-0.88) with a significant trend (P = 0.01) through the quartiles. Although enterolactone plasma concentrations were 10-fold higher, enterolactone's reduction in risk was not statistically significant (P for trend = 0.09). Use of oral antibiotic therapy could decrease the plasma concentrations of enterolactone. Exclusion of antibiotic users resulted in similar odds ratios for both enterolignans, but the association for enterolactone became somewhat stronger (P = 0.05 versus P = 0.09). We observed a substantial reduction in colorectal adenoma risk among subjects with high plasma concentrations of enterolignans, in particular, enterodiol. These findings could be important in the prevention of colorectal adenomas.

Topics: 4-Butyrolactone; Adenoma; Case-Control Studies; Chromatography, Liquid; Colorectal Neoplasms; Diet; Female; Humans; Incidence; Lignans; Middle Aged; Netherlands; Odds Ratio; Retrospective Studies; Spectrometry, Mass, Electrospray Ionization; Surveys and Questionnaires

The natural product justicidin A, an arylnaphthalide lignan isolated from Justicia procumbens, significantly inhibited the growth of human colorectal cancer cells HT-29 and HCT 116 at day 6 post-treatment. Further study revealed that justicidin A-treated HT-29 and HCT 116 colorectal cancer cells died of apoptosis. Justicidin A treatment caused DNA fragmentation and an increase in phosphatidylserine exposure of the cells. The number of cells in the sub-G1 phase was also increased upon justicidin A treatment. Caspase-9 but not caspase-8 was activated, suggesting that justicidin A treatment damaged mitochondria. The mitochondrial membrane potential was altered and cytochrome c and Smac were released from mitochondria to the cytoplasm upon justicidin A treatment. The level of Ku70 in the cytoplasm was decreased, but that of Bax in mitochondria was increased by justicidin A. Since Ku70 normally binds and sequesters Bax, these results suggest that justicidin A decreases the level of Ku70 leading to translocation of Bax from the cytosol to mitochondria to induce apoptosis. Oral administration of justicidin A was shown to suppress the growth of HT-29 cells transplanted into NOD-SCID mice, suggesting chemotherapeutic potential of justicidin A on colorectal cancer cells.

Topics: Animals; Antigens, Nuclear; Apoptosis; bcl-2-Associated X Protein; Cell Cycle; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Cyclosporine; Cytoplasm; Dioxolanes; DNA-Binding Proteins; Female; G1 Phase; Humans; Ku Autoantigen; Lignans; Mice; Mice, Nude; Mitochondria; Protein Transport; Proto-Oncogene Proteins c-bcl-2; Transplantation, Heterologous; Uterine Cervical Neoplasms

To investigate the signal pathway of honokiol-induced apoptosis on human colorectal carcinoma RKO cells and to evaluate whether p53 and p53-related genes were involved in honokiol-treated RKO cells.. Cell cycle distribution and subdiploid peak were analyzed with a flow cytometer and DNA fragment with electrophoresis on agarose gels. Transcriptional level of Bax, Bcl-2, Bid and Bcl-xl was accessed by RT-PCR. Western blotting was used to measure p53 protein expression and other factors related to apoptosis. Proliferation inhibition of two cell lines (RKO, SW480) with high expression of p53 and one cell line with p53 negative expression (LS180) was monitored by MTT assay.. Honokiol induced RKO cell apoptosis in a dose-dependent manner. The mRNA expression level and protein level of Bid were up-regulated while that of Bcl-xl was down-regulated, but no changes in Bax and Bcl-2 were observed. Western blotting showed p53 expression had no remarkable changes in honokiol-induced RKO cell apoptosis. LS180 cells treated with honokiol exhibited apparent growth inhibition like RKO cells and Sw480 cells.. Honokiol can induce RKO cells apoptosis through activating caspase cascade by p53-indepenent pathway.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Colorectal Neoplasms; Humans; Lignans; Tumor Suppressor Protein p53

To investigate the anticancer activity of honokiol on RKO, a human colorectal carcinoma cell line in vitro and in vivo, and to evaluate its possible use in clinic.. In vitro anticancer activity of honokiol was demonstrated by its induction of apoptosis in tumor cells. We analyzed cell proliferation with MTT assay, cell cycle with flow cytosmeter, DNA fragment with electrophoresis on agarose gels. To test the mechanism of honokiol-induced apoptosis, Western blotting was used to investigate the factors involved in this process. The pharmacokinetics study of honokiol was tested by high phase liquid chromatography. In in vivo study, Balb/c nude mice were incubated with RKO cells. Honokiol was injected intraperitoneally every other day into tumor bearing Balb/c nude mice.. Our results showed that honokiol induced apoptosis of RKO cells in a time- and dose-dependent manner. At 5-10 microg/mL for 48 h, honokiol induced apoptosis through activating Caspase cascades. Pharmacokinetics study demonstrated that, honokiol could be absorbed quickly by intraperitoneal injection, and maintained in plasma for more than 10 h. In nude mice bearing RKO-incubated tumor, honokiol displayed anticancer activity by inhibiting tumor growth and prolonging the lifespan of tumor bearing mice.. With its few toxicity to normal cells and potent anticancer activity in vitro and in vivo, honokiol might be a potential chemotherapy candidate in treating human colorectal carcinoma.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Blotting, Western; Caspase 3; Caspase 9; Caspases; Cell Division; Cell Line, Tumor; Colorectal Neoplasms; DNA Fragmentation; Drugs, Chinese Herbal; Humans; Lignans; Mice; Mice, Inbred BALB C; Mice, Nude; Xenograft Model Antitumor Assays

Phytoestrogens, like isoflavonoids and lignans, have been postulated as possible colorectal cancer protective constituents. To investigate this hypothesis, two high-fiber sources rich in lignan precursors, i.e., rye bran and flaxseed, were tested for their ability to modulate intestinal tumor development in ApcMin mice. Test diets consisted of a control diet (a Western-style diet, adjusted for fiber and/or phytate content) supplemented with 5% flaxseed or 30% rye bran. Chemical analysis of diets and blood samples confirmed the enhanced systemic exposure of mice fed the test diets to the major lignan precursors, i.e., secoisolariciresinol and matairesinol. No statistically significant difference was observed in the incidence and multiplicity of small intestinal and colon tumors at terminal sacrifice between mice fed the control diet or the diet supplemented with 5% flaxseed. With the rye bran diet a statistically significant enhancement of the number of small intestinal tumors in female mice was observed. The number of colon tumors, however, was comparable between the control and rye bran-fed mice of either sex. Furthermore, no activating point mutations in the K-ras oncogene nor positive immunohistochemical staining for the p53 gene were observed in a set of 48 colon tumors. In conclusion, our results demonstrate that increased intake of lignan precursors from flaxseed or rye bran, administered in a Western-style diet, does not protect against intestinal tumor development in an appropriate animal model for intestinal neoplasia such as the ApcMin mice.

Topics: Animals; Colorectal Neoplasms; Diet; Disease Models, Animal; Female; Flax; Genes, APC; Intestinal Neoplasms; Isoflavones; Lignans; Male; Mice; Mice, Mutant Strains; Mutation; Random Allocation; Secale; Seeds

Plant-derived lignans caused cell loss by apoptosis in colorectal adenoma and carcinoma cells. Nordihydroguaiaretic acid (NDGA), commonly used for the inhibition of lipoxygenase isoenzymes, showed the strongest growth inhibition with an IC50 of 1.9+/-0.5 microg followed by epiashantin (IC50=9.8+/-4.5 microM) and arctigenin (IC50=16.5+/-8.5 microM). The lignans caused a time- and dose-dependent loss of mitochondrial membrane potential (MMP), down regulation of the anti-apoptotic protein bcl(xl) and an increase of the apoptotic index. The time interval until loss of MMP and down modulation of bcl(xl) became evident correlated with the efficiency of growth inhibition by NDGA, epiashantin and yangambin. Bcl2 and caspase 3 were not involved. NDGA also induced a shift of the culture population to the G2/M phase of the cell cycle. With respect to these results, naturally occurring lignans could be useful in the therapy and chemoprevention of colorectal tumors.

Topics: Adenoma; Animals; Apoptosis; Carcinoma; Cell Cycle; Cell Line; Cell Line, Tumor; Colorectal Neoplasms; Dose-Response Relationship, Drug; Inhibitory Concentration 50; Intestinal Mucosa; Lignans; Lipoxygenase Inhibitors; Masoprocol; Phytotherapy; Plant Extracts; Plant Structures; Plants, Medicinal; Rats

A new lignan glycoside, 1,5-dihydroxy-2-(4"-beta-D-glucopyranosyloxy-3"-methoxyphenyl)-6-(4'-hydroxy-3'-methoxyphenyl)-3,7-dioxabicyclo[3.3.0]octane, named ambrosidine ([structure: see text]), along with seven known compounds (four iridoids and three hydroxycinnamic esters) were isolated from the roots of Cephalaria ambrosioides. The structures of these compounds were determined by use of NMR and MS techniques and by chemical transformations. The cytotoxic activity of the novel compound [structure: see text] was evaluated against five human solid tumour cell lines.

Topics: Acetylation; Antineoplastic Agents, Phytogenic; Cell Survival; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Glucosides; Greece; Humans; Hydrolysis; Iridoids; Lignans; Magnoliopsida; Male; Mass Spectrometry; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Plant Roots; Plants, Medicinal; Prostatic Neoplasms; Tumor Cells, Cultured