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    Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia. Deschner E E,Ruperto J,Wong G,Newmark H L Carcinogenesis Dietary quercetin (QU) and rutin (RU), phenolic flavonoids commonly found in many fruits and vegetables, were provided to CF1 female mice for 50 weeks to assess the ability of these compounds to inhibit azoxymethanol (AOM)-induced colonic neoplasia. In addition to a control group fed an AIN 76A diet, five other groups received that diet to which was added either 0.1, 0.5 or 2.0% QU and 1.0 or 4.0% RU. Acute studies revealed that, among saline controls, no alteration of any proliferative parameters of colonic epithelial cells was observed among those groups receiving any dose of QU or RU. However, among the AOM-treated mice, both 2% QU and 4% RU significantly reduced hyperproliferation and inhibited the shift of S-phase cells to the middle and upper portion of crypts. Moreover, mice fed these concentrations of QU and RU had significantly fewer AOM-induced focal areas of dysplasia (FADs) than those fed the control diet (0.2 +/- 0.4 and 0.4 +/- 0.5 versus 3.6 +/- 2.3 respectively). Tumors occurred more frequently in the distal half of the colon, regardless of treatment. Compared with controls, mice fed 2% QU had a significantly reduced tumor incidence (25.0% versus 5.9%, P = 0.03). Those fed 4% RU showed only a trend toward inhibition (25% versus 9.7%, P = 0.11). Nevertheless, both 2% QU and 4% RU suppressed tumor multiplicity, i.e. fewer tumors/animal arose in these groups than in the AOM-treated control mice (1.2 versus 2.3, P = 0.005; 1.1 versus 2.3, P = 0.003 respectively). Clearly, QU and RU exhibit significant activity in reducing AOM-induced hyperproliferation of colonic epithelial cells and FAD incidence. This behavior successfully forecast the ability of both flavonoids to suppress tumor multiplicity and ultimately tumor development. 10.1093/carcin/12.7.1193
    The effect of dietary quercetin and rutin on AOM-induced acute colonic epithelial abnormalities in mice fed a high-fat diet. Deschner E E,Ruperto J F,Wong G Y,Newmark H L Nutrition and cancer Dietary quercetin (QU) and rutin (RU), phenolic flavonoids found in many fruits and vegetables, when fed to mice on a low-fat diet successfully modified the response to azoxymethanol (AOM) by initially inhibiting hyperproliferation and the formation of foci of dysplasia (FADs) and ultimately reducing tumor incidence (Carcinogenesis 12, 1193-1196, 1991). In this study, we tested the efficacy of QU and RU when a high-fat diet was presented. An AIN 76A diet made with 20% corn oil (CO) was supplemented with QU (0.5%, 2.0%, or 5.0%) and RU (2.0% or 4.0%). These five diets, as well as a 5.0% and a 20.0% CO diet, were fed to a group of CF1 female mice for nine weeks. Both QU and RU showed nonsignificant dose-related trends toward normalization of the AOM-induced upward extension of S phase cells. Examination of 500 microns of serially sectioned distal colon revealed that 29% of mice fed the 20% CO control diet were free of FADs. Among the mice fed QU, regardless of dose, > 80% were free of FADs. When the three groups fed QU were pooled and compared with the control 20% CO-fed mice, the degree of protection was significant (p < 0.01). Mice fed RU expressed a level of protection that bordered on the significant (p < 0.08). These data suggest that, regardless of the fat content of the diet, QU and RU are capable of modifying or inhibiting events in the development of chemically induced colonic neoplasia. 10.1080/01635589309514287
    Dietary flavonoids protect human colonocyte DNA from oxidative attack in vitro. Duthie S J,Dobson V L European journal of nutrition BACKGROUND & AIMS:Epidemiological studies suggest that antioxidant polyphenols in the human diet may protect against diseases such as cancer. In this study we investigated the cytoprotective potential of the flavonoids, quercetin, myricetin, kaempferol and rutin against oxidative DNA damage in human colonocytes in vitro. METHODS:Caco-2 cells, which display specialised enterocyte/colonocyte cell functions, were used as an in vitro model for human colonocytes. Hydrogen peroxide was employed as the oxidant. DNA damage (strand breakage, oxidised purines and oxidised pyrimidines) was determined using the alkaline single cell gel electrophoresis or comet assay. Cell growth and viability were measured. RESULTS:Hydrogen peroxide caused a dose-dependent increase in DNA strand breakage in human colonocytes, presumably via oxygen free radical generation. Quercetin and myricetin protected Caco-2 cells against oxidative attack. In addition, quercetin decreased hydrogen peroxide-mediated inhibition of growth. Neither rutin nor kaempferol was effective. However, quercetin, while inhibiting DNA strand breakage, did not alter the levels of oxidised bases following peroxide treatment. The antifungal agent ketoconazole, prevented quercetin cytoprotection in Caco-2 cells, indicating that P450-mediated metabolism may alter the efficacy of the flavonoids against oxidative DNA damage. CONCLUSION:Flavonoids, particularly quercetin, the most abundant flavonoid in the human diet, are likely to be important in defending human colonocytes from oxidative attack. 10.1007/s003940050043
    [Effect of antioxidants on human primary and metastatic colon cancer cells at hypoxia and normoxia]. Mielczarek-Puta Magdalena,Chrzanowska Alicja,Otto-Ślusarczyk Dagmara,Graboń Wojciech,Barańczyk-Kuźma Anna Wiadomosci lekarskie (Warsaw, Poland : 1960) THE AIM:Evaluation of some antioxidants on human colon cancer cells viability and proliferation at various oxygen levels. MATERIAL AND METHODS:Human primary (SW480) and metastatic (SW620) colon cancer cells were cultured at hypoxia (1% oxygen), tissues (10% oxygen) and atmospheric (21% oxygen) normoxia with quercetin, epigallocatechin gallate, lipoic acid, hydroxycitric acid, their mixture, and without studied compounds (control). Antioxidants were used at physiological concentrations. The cell viability was determined by trypan blue dye exclusion and proliferation by MTT assay. RESULTS:The viability of each line ranged from 80% to 97%, and it was independent on the compound and oxygen availability. At hypoxia the cell count of both lines was lower than for the controls in the presence of each studied compound. At tissue normoxia the cell count of primary cancer cells was decreased only with epigallocatechin gallate, whereas metastatic cells were sensitive for each antioxidant. CONCLUSIONS:Our results indicated, that the studied antioxidants were not cytotoxic at physiological levels for both pirmary and metastatic colon cancer. Their cytostatic effect depend on the type of cell, oxygen availability and antioxidant concentration.
    The flavonol isorhamnetin exhibits cytotoxic effects on human colon cancer cells. Jaramillo Sara,Lopez Sergio,Varela Lourdes M,Rodriguez-Arcos Rocio,Jimenez Ana,Abia Rocio,Guillen Rafael,Muriana Francisco J G Journal of agricultural and food chemistry The aim of this study was to determine whether isorhamnetin, an immediate 3'-O-methylated metabolite of quercetin, affects proliferation, cell death, and the cell cycle of human colon carcinoma (HCT-116) cells. Isorhamnetin was found to be a potent antiproliferative agent in a dose- and time-dependent manner, with an IC50 of 72 μM after 48 h of incubation as estimated by MTT assay. Flow cytometry and fluorescence microscopy analysis showed that isorhamnetin exerted a stimulatory effect on apoptosis and necrosis. Isorhamnetin also increased the number of cells in G2/M phase. Serum deprivation appeared to potentiate the effects of isorhamnetin on cell death and facilitated cell cycle progression to G0/G1 phase. These results suggest that isorhamnetin might mediate inhibition of HCT-116 cell growth through the perturbation of cell cycle progression and are consistent with the notion that G2/M checkpoints could be a conserved target for flavonoids in human colon cancer cells, leading to apoptotic and necrotic death. These antiproliferative, apoptotic, necrotic, and cell cycle effects suggest that isorhamnetin may have clinically significant therapeutic and chemopreventive capabilities. To our knowledge, this is the first report of the effect of isorhamnetin on human colon cancer cells. 10.1021/jf102669p
    Induction of apoptosis in colon cancer cells treated with isorhamnetin glycosides from Opuntia ficus-indica pads. Antunes-Ricardo Marilena,Moreno-García Beatriz E,Gutiérrez-Uribe Janet A,Aráiz-Hernández Diana,Alvarez Mario M,Serna-Saldivar Sergio O Plant foods for human nutrition (Dordrecht, Netherlands) (OFI) contains health-promoting compounds like flavonoids, being the isorhamnetin glycosides the most abundant. We evaluated the effect of OFI extracts with different isorhamnetin glycosides against two different human colon cancer cells (HT-29 and Caco2). The extracts were obtained by alkaline hydrolysis with NaOH at 40 °C during 15, 30 or 60 min. Tri and diglycosides were the most abundant isorhamnetin glycosides, therefore these compounds were isolated to compare their cytotoxic effect with the obtained from the extracts. The OFI extracts and purified isorhamnetin glycosides were more cytotoxic against HT-29 cells than Caco2 cells. OFI-30 exhibited the lowest IC50 value against HT-29 (4.9 ± 0.5 μg/mL) and against Caco2 (8.2 ± 0.3 μg/mL). Isorhamnetin diglycosides IG5 and IG6 were more cytotoxic than pure isorhamnetin aglycone or triglycosides when they were tested in HT-29 cells. Bioluminescent analysis revealed increased activity of caspase 3/7 in OFI extracts-treated cells, particularly for the extract with the highest concentration of isorhamnetin triglycosides. Flow cytometry analysis confirmed that OFI extract and isorhamnetin glycosides induced a higher percentage of apoptosis in HT-29 than in Caco2, while isorhamnetin was more apoptotic in Caco2. This research demonstrated that glycosilation affected antiproliferative effect of pure isorhamnetin glycosides or when they are mixed with other phytochemicals in an extract obtained from OFI. 10.1007/s11130-014-0438-5
    Flavonoids uptake and their effect on cell cycle of human colon adenocarcinoma cells (Caco2). Salucci M,Stivala L A,Maiani G,Bugianesi R,Vannini V British journal of cancer Green tea, mainly through its constituents epigallocatechin gallate, epigallocatechin, epicatechin gallate and epicatechin, has demonstrated anticarcinogenic activity in several animal models, including those for skin, lung and gastro-intestinal tract cancer, although less is known about colorectal cancer. Quercetin, the major flavonoid present in vegetables and fruit, exerts potential anticarcinogenic effects in animal models and cell cultures, but less is known about quercetin glucosides. The objectives of this study were to investigate (i) the antioxidant activity of the phenolic compounds epicatechin, epigallocatechin gallate, gallic acid and quercetin-3-glucoside; (ii) the cytotoxicity of different concentrations of epicatechin, epigallocatechin gallate, and gallic acid; (iii) the cellular uptake of epicatechin, epigallocatechin gallate, gallic acid and quercetin-3-glucoside and (iv) their effect on the cell cycle. Human colon adenocarcinoma cells were used as experimental model. The results of this study indicate that all dietary flavonoids studied (epicatechin, epigallocatechin gallate, gallic acid and quercetin-3-glucoside) show a significant antioxidant effect in a chemical model system, but only epigallocatechin gallate or gallic acid are able to interfere with the cell cycle in Caco2 cell lines. These data suggest that the antioxidant activity of flavonoids is not related to the inhibition of cellular growth. From a structural point of view, the galloyl moiety appears to be required for both the antioxidant and the antiproliferative effects. 10.1038/sj.bjc.6600295
    Impact of quercetin and EGCG on key elements of the Wnt pathway in human colon carcinoma cells. Pahlke Gudrun,Ngiewih Yufanyi,Kern Melanie,Jakobs Sandra,Marko Doris,Eisenbrand Gerhard Journal of agricultural and food chemistry The flavonoids quercetin (QUE) and (-)-epigallocatechin-3-gallate (EGCG) are discussed as potential chemopreventive food constituents. Both compounds have been shown to affect a spectrum of different cellular signaling pathways. Glycogen synthase kinase-3beta (GSK3beta) is one of the key elements of the Wnt pathway, governing beta-catenin homeostasis. The inhibition of GSK3 kinase activity might lead to the onset of beta-catenin/TCF/LEF-mediated gene transcription, representing a potentially mitogenic stimulus. The aim of the study was to elucidate whether QUE and EGCG possibly mediate undesired proliferative stimuli in human colon carcinoma cells by interference with the Wnt pathway. In HT29 cells QUE did not inhibit the activity of GSK3alpha and -beta, measured as phosphorylation at Ser21 and Ser9, respectively. In accordance, QUE did not substantially affect beta-catenin homeostasis. In a reporter gene assay QUE was found to act as a weak inductor of T-cell factor/lymphoid enhancer factor (TCF/LEF) mediated luciferase expression, which was, however, not associated with a stimulation of cell growth. Treatment of HT29 cells with EGCG led to a potent inhibition of GSK3alpha and -beta activity. Subsequently, the amount of phosphorylated beta-catenin was diminished in a concentration-dependent manner. Concomitantly, the overall amount of beta-catenin was decreased to a similar extent, which might result from a downregulation of beta-catenin neogenesis, indicated by reduced levels of beta-catenin mRNA. In accordance, no induction of TCF/LEF-mediated luciferase expression was observed. In conclusion, the results allow the assumption that QUE and EGCG do not mediate proliferative stimuli in HT29 cells by interference with key elements of the Wnt pathway. 10.1021/jf0612530
    Isoquercitrin suppresses colon cancer cell growth in vitro by targeting the Wnt/β-catenin signaling pathway. Amado Nathália G,Predes Danilo,Fonseca Barbara F,Cerqueira Débora M,Reis Alice H,Dudenhoeffer Ana C,Borges Helena L,Mendes Fábio A,Abreu Jose G The Journal of biological chemistry Flavonoids are plant-derived polyphenolic molecules that have potential biological effects including anti-oxidative, anti-inflammatory, anti-viral, and anti-tumoral effects. These effects are related to the ability of flavonoids to modulate signaling pathways, such as the canonical Wnt signaling pathway. This pathway controls many aspects of embryonic development and tissue maintenance and has been found to be deregulated in a range of human cancers. We performed several in vivo assays in Xenopus embryos, a functional model of canonical Wnt signaling studies, and also used in vitro models, to investigate whether isoquercitrin affects Wnt/β-catenin signaling. Our data provide strong support for an inhibitory effect of isoquercitrin on Wnt/β-catenin, where the flavonoid acts downstream of β-catenin translocation to the nuclei. Isoquercitrin affects Xenopus axis establishment, reverses double axes and the LiCl hyperdorsalization phenotype, and reduces Xnr3 expression. In addition, this flavonoid shows anti-tumoral effects on colon cancer cells (SW480, DLD-1, and HCT116), whereas exerting no significant effect on non-tumor colon cell (IEC-18), suggesting a specific effect in tumor cells in vitro. Taken together, our data indicate that isoquercitrin is an inhibitor of Wnt/β-catenin and should be further investigated as a potential novel anti-tumoral agent. 10.1074/jbc.M114.621599
    Estrogen synthesis in human colon cancer epithelial cells. Fiorelli G,Picariello L,Martineti V,Tonelli F,Brandi M L The Journal of steroid biochemistry and molecular biology Epidemiological and experimental data suggest an involvement of estrogen in the development and progression of colorectal cancer. In order to determine whether local synthesis of estrogen occurred in human colonic cancer cells, two colorectal cancer cell lines, HCT8 and HCT116, were evaluated for gene expression and enzyme activity of cytochrome P450 aromatase. In addition, the effect on aromatase expression of charcoal-stripped fetal calf serum, of quercetin and genistein and of tamoxifen and raloxifene was investigated in both cell lines. RT-PCR analysis revealed that colorectal adenocarcinoma cell lines contain aromatase as a major component. The conversion of [(3)H]-androstenedione to estrone and labeled water was dose-dependently inhibited by 4-hydroxyandrostenedione and obeyed Michaelis-Menten kinetic with apparent Km values of approximately 20 nM and V(max) values of approx. 200 and 500 fmol/mg protein/h for HCT8 and HCT116 cells, respectively. After 24 h incubation, genistein (1 microM) significantly increased aromatase activity in HCT8 cells, with no effect on HCT116 cells. In accord with previous observation in reproductive tissues, quercetin (1 microM) significantly inhibited the enzyme activity in both cell lines. Also tamoxifen (100 nM) acted as inhibitor, while raloxifene (10 nM) decreased the enzyme activity only in HCT116 cells. The aromatase gene expression modulation by these effective agents was consistent with their effects on enzyme activity. These findings demonstrate for the first time that colorectal adenocarcinoma cell lines express aromatase. Interestingly, the enzyme activity was inhibited by quercetin, one major dietary flavonoid, by tamoxifen, a hormonal therapeutic agent for breast cancer, and by raloxifene, used in the prevention of postmenopausal osteoporosis.
    Taxifolin curbs NF-κB-mediated Wnt/β-catenin signaling via up-regulating Nrf2 pathway in experimental colon carcinogenesis. Manigandan Krishnan,Manimaran Dharmar,Jayaraj Richard L,Elangovan Namasivayam,Dhivya Velumani,Kaphle Anubhav Biochimie Aberrations in homeostasis mechanisms including Nrf2, inflammatory, and Wnt/β-catenin signaling are the major causative factors implicated in colon cancer development. Hence blocking these pathways through natural interventions pave a new channel for colon cancer prevention. Earlier, we reported the chemopreventive effect of taxifolin (TAX) against colon carcinogenesis. In this study, we aimed to understand the ability of TAX, to modulate the Nrf2, inflammatory and Wnt/β-catenin cascades on 1, 2-dimethyl hydrazine (DMH)-induced mouse colon carcinogenesis. In addition, in silico molecular docking studies were performed to evaluate the binding affinity between TAX and target proteins (Nrf2, β-catenin, and TNF-α). We perceived that the increase of serum marker enzyme levels (CEA and LDH) and mast cell infiltration that occurs in the presence of DMH is inverted after TAX treatment. Immunoblot expression and docking analysis revealed that TAX could induce antioxidant response pathway, confirming the enhanced level of Nrf2 protein. It also inhibited NF-κB and Wnt signaling by down-regulating the levels of regulatory metabolites such as TNF-α, COX-2, β-catenin, and Cyclin-D1. Collectively, results of our hypothesis shown that TAX is an effective chemopreventive agent capable of modulating inflammatory, Wnt and antioxidant response pathway proteins in tumor microenvironment which explicating its anticancer property. 10.1016/j.biochi.2015.10.014
    Isorhamnetin glycoside isolated from Opuntia ficus-indica (L.) MilI induces apoptosis in human colon cancer cells through mitochondrial damage. Antunes-Ricardo Marilena,Hernández-Reyes Annia,Uscanga-Palomeque Ashanti C,Rodríguez-Padilla Cristina,Martínez-Torres Ana Carolina,Gutiérrez-Uribe Janet Alejandra Chemico-biological interactions This work aimed to evaluate the mechanisms involved in the apoptosis induction of isorhamnetin-3-O-glucosyl-pentoside (IGP) in metastatic human colon cancer cells (HT-29). To achieve this, we assessed phosphatidylserine (PS) exposure, cell membrane disruption, chromatin condensation, cell cycle alterations, mitochondrial damage, ROS production, and caspase-dependence on cell death. Our results showed that IGP induced cell death on HT-29 cells through PS exposure (48%) and membrane permeabilization (30%) as well as nuclear condensation (54%) compared with control cells. Moreover, IGP treatment induced cell cycle arrest in G2/M phase. Bax/Bcl-2 ratio increased and the loss of mitochondrial membrane potential (63%) was observed in IGP-treated cells. Finally, as apoptosis is a caspase-dependent cell death mechanism, we used a pancaspase-inhibitor (Q-VD-OPh) to demonstrate that the cell death induced by IGP was caspase-dependent. Overall these results indicated that IGP induced apoptosis through caspase-dependent mitochondrial damage in HT-29 colon cancer cells. 10.1016/j.cbi.2019.108734
    Isorhamnetin Inhibits Reactive Oxygen Species-Dependent Hypoxia Inducible Factor (HIF)-1α Accumulation. Seo Suho,Seo Kyuhwa,Ki Sung Hwan,Shin Sang Mi Biological & pharmaceutical bulletin Isorhamnetin is a flavonoid metabolite of quercetin and isolated from water dropwort (Oenanthe javanica, Umbelliferae). It has been reported that isorhamnetin exerts beneficial effects including antioxidant, anti-inflammatory, and anti-proliferative activities. The present study investigated whether the antioxidant activity of isorhamnetin is correlated with its anti-cancer effects on colorectal cancer cells. Isorhamnetin significantly repressed cobalt chloride (CoCl)- or hypoxia-induced hypoxia inducible factor-1α (HIF-1α) accumulation in HCT116 and HT29 cells. When compared with quercetin, isorhamnetin showed potent inhibition of HIF-1α. Moreover, it inhibited CoCl-induced activity of hypoxia response element reporter gene and HIF-1α-dependent transcription of genes such as glucose transporter 1, lactate dehydrogenase A, carbonic anhydrase-IX, and pyruvate dehydrogenase kinase 1. Isorhamnetin also blocked hydrogen peroxide (HO)-induced HIF-1α accumulation. The antioxidant effects of isorhamnetin were confirmed by observation of CoCl- or HO-induced reactive oxygen species (ROS) production. Consistently, overexpressed HIF-1α was decreased by isorhamnetin or N-acetyl-L-cysteine in HEK293 cells. In vitro migration and invasion assay further confirmed the inhibitory effects of isorhamnetin on cancer cells. Collectively, these results demonstrate that isorhamnetin inhibits ROS-mediated HIF-1α accumulation, which contributes to its anti-metastatic efficacy. 10.1248/bpb.b16-00414
    Antitumor activities of quercetin and quercetin-5',8-disulfonate in human colon and breast cancer cell lines. Zhang Haisheng,Zhang Min,Yu Linhong,Zhao Yan,He Nianwu,Yang Xingbin Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association This study is designed to compare the anticancer effects of quercetin and its water-soluble sulfated derivative, quercetin-5',8-disulfonate (QS), in human colon cancer LoVo cells and breast cancer MCF-7 cells. It was found that both quercetin and QS can inhibit the growth of cancer cells in a dose-dependent manner, with the IC(50) values of 40.2 and 28.0 μM for LoVo cells and 30.8 and 19.9 μM for MCF-7 cells, respectively, suggesting QS was more effective against the cancer cells than quercetin. Moreover, flow cytometric assay revealed that quercetin and QS could mediate the cell-cycle arrest principally in the S phase after 24h of treatment with the two tumor cells. It was also found that 69.6% of LoVo cells and 90.6% of MCF-7 cells entered the early phase of apoptosis when treated with 100 μM QS for 48 h. Furthermore, we firstly found the generation of ROS is a critical mediator in QS-induced cell growth inhibition. Taken together, the novel sulfated derivative of quercetin possesses strong antitumor activity via a ROS-dependent apoptosis pathway, and has the excellent potential to be developed into an antitumor precursor compound. 10.1016/j.fct.2012.01.025
    Apoptotic Effects of Quercitrin on DLD-1 Colon Cancer Cell Line. Cincin Zeynep Birsu,Unlu Miray,Kiran Bayram,Bireller Elif Sinem,Baran Yusuf,Cakmakoglu Bedia Pathology oncology research : POR Quercetin, which is the most abundant bioflavonoid compound, is mainly present in the glycoside form of quercitrin. Although different studies indicated that quercitrin is a potent antioxidant, the action of this compound is not well understood. In this study, we investigated whether quercitrin has apoptotic and antiproliferative effects in DLD-1 colon cancer cell lines. Time and dose dependent antiproliferative and apoptotic effects of quercitrin were subsequently determined by WST-1 cell proliferation assay, lactate dehydrogenase (LDH) cytotoxicity assay, detection of nucleosome enrichment factor, changes in caspase-3 activity, loss of mitochondrial membrane potential (MMP) and also the localization of phosphatidylserine (PS) in the plasma membrane. There were significant increases in caspase-3 activity, loss of MMP, and increases in the apoptotic cell population in response to quercitrin in DLD-1 colon cancer cells in a time- and dose-dependent manner. These results revealed that quercitrin has antiproliferative and apoptotic effects on colon cancer cells. Quercitrin activity supported with in vivo analyses could be a biomarker candicate for early colorectal carcinoma. 10.1007/s12253-014-9825-3
    CHNQ, a novel 2-Chloro-1,4-naphthoquinone derivative of quercetin, induces oxidative stress and autophagy both in vitro and in vivo. Enayat Shabnam,Şeyma Ceyhan M,Taşkoparan Betül,Stefek Milan,Banerjee Sreeparna Archives of biochemistry and biophysics Quercetin (Qc) shows strong antitumor effects but has limited clinical application due to poor water solubility and bioavailability. In a screening of novel semi-synthetic derivatives of Qc, 3,7-dihydroxy-2-[4-(2-chloro-1,4-naphthoquinone-3-yloxy)-3-hydroxyphenyl]-5-hydroxychromen-4-one (CHNQ) could ameliorate acetic acid induced acute colitis in vivo more efficiently than Qc. Since inflammation contributes to colorectal cancer (CRC), we have hypothesized that CHNQ may have anti-cancer effects. Using CRC cell lines HCT-116 and HT-29, we report that CHNQ was three-fold more cytotoxic than Qc along with a robust induction of apoptosis. As expected from naphthoquinones such as CHNQ, a strong induction of oxidative stress was observed. This was accompanied by reactive oxygen species (ROS) induced autophagy marked by a dramatic increase in the lipidation of LC3, decreased activation of Akt/PKB, acidic vesicle accumulation and puncta formation in HCT-116 cells treated with CHNQ. Interestingly, an incomplete autophagy was observed in HT-29 cells where CHNQ treatment led to LC3 lipidation, but not the formation of acidic vacuoles. CHNQ-induced cytotoxicity, ROS formation and autophagy were also detected in vivo in Saccharomyces cerevisiae strain RDKY3615 (WinstonS288C background). Overall, we propose that CHNQ can induce cancer cell death through the induction of oxidative stress, and may be examined further as a potential chemotherapeutic drug. 10.1016/j.abb.2016.03.004
    Novel quercetin derivative TEF induces ER stress and mitochondria-mediated apoptosis in human colon cancer HCT-116 cells. Khan Imran,Paul Souren,Jakhar Rekha,Bhardwaj Monika,Han Jaehong,Kang Sun Chul Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Although quercetin is very well known for its anticancer activity, however it shows some drawbacks. Herein, we have evaluated the apoptotic effect TEF (5, 3'-dihydroxy-3, 7, 4'-triethoxyflavone), a newly synthesized quercetin derivative on HCT-116 colon cancer cells. After 24h of treatment, the proliferation of colon cancer cells was inhibited by TEF. TEF induced apoptosis, as confirmed by the presence of fragmented nuclei, reduced mitochondrial membrane potential, and elevated cytoplasmic and mitochondrial reactive oxygen species (ROS) levels. TEF treatment causes elevation of IRE1-α and activates calcium ions (Ca) with concomitant increase in JNK levels. Elevated Ca ion translocates from ER to mitochondria which leads to ROS release and oxidative stress. TEF treatment further elevated levels of pro-apoptotic factors and down-regulated the level of Bcl2. TEF led to activation of mito-JNK (mitochondrial JNK), which plays a crucial role in activation of oxidative stress and caspase mediated apoptotic cell death. Moreover, JNK inhibition shown to suppress TEF induced apoptosis in HCT-116 colon cancer cells. Therefore, this study reveals the apoptotic role of TEF against HCT-116 cell line via IRE1-α and mito-JNK pathway. 10.1016/j.biopha.2016.09.094
    Isorhamnetin suppresses colon cancer cell growth through the PI3K‑Akt‑mTOR pathway. Li Chuan,Yang Xi,Chen Cheng,Cai Shaoxin,Hu Junbo Molecular medicine reports Isorhamnetin, a flavonoid isolated from the fruits of herbal medicinal plants, such as Hippophae rhamnoides L., exerts anticancer effects similar to other flavonoids. However, the effect of isorhamnetin on colorectal cancer (CRC) and the underlying molecular mechanism are unclear. This study aimed to determine the effect of isorhamnetin on the proliferation of cells from the human CRC cell lines, HT‑29, HCT116 and SW480. It was demonstrated that isorhamnetin suppressed the proliferation of cells from all three cell lines, induced cell cycle arrest at the G2/M phase and suppressed cell proliferation by inhibiting the PI3K‑Akt‑mTOR pathway. Isorhamnetin also reduced the phosphorylation levels of Akt (ser473), phosph‑p70S6 kinase and phosph‑4E‑BP1 (t37/46) protein, and enhanced the expression of Cyclin B1 protein. Therefore, this compound was revealed to be a selective PI3K‑Akt‑mTOR pathway inhibitor, and may be a potent anticancer agent for the treatment of CRC, as it restrains the proliferation of CRC cells. 10.3892/mmr.2014.1886
    3, 3'-Dimethylquercetin Inhibits the Proliferation of Human Colon Cancer RKO Cells through Inducing G2/M Cell Cycle Arrest and Apoptosis. Wu Jianguo,Yi Jun,Wu Yanbin,Chen Xuzheng,Zeng Jianwei,Wu Jinzhong,Peng Wei Anti-cancer agents in medicinal chemistry BACKGROUND:Our previous study successfully identified that 3,3'-Dimethylquercetin (DMQ) acted as a potent anticancer agent against human colon cancer cell lines RKO. Thus, this study was conducted to investigate the underlying mechanism by which DMQ displayed inhibitory activity in RKO cells. METHODS:Flow cytometry was used to evaluate the effect of DMQ on the cell cycle arrest, as well as the mitochondrial membrane potential in RKO cells. DAPI staining and DNA fragmentation ladder assays were performed to assess the apoptosis inducing activity of DMQ. Furthermore, western blot analysis was conducted to examine the expression of related proteins responsible for the cell cycle arrest and apoptosis. RESULTS:Treatment with DMQ caused a significant increase in the fraction of G2/M cells, and induced remarkable apoptosis. Furthermore, western blot analysis showed that DMQ arrested cells at G2/M checkpoint by down-regulation of cyclin B1, cdc2 and cdc25c and up-regulation of p21, and induced cell apoptosis via affecting the ratio of Bax/Bcl-2, causing loss of the mitochondrial membrane potential and enhancing the expression of cleaved caspase-9 (C-caspase-9) and cleaved caspase-3 (C-caspase-3). CONCLUSION:These data showed that DMQ could suppress RKO cell growth by arresting RKO cells at G2/M checkpoint and inducing mitochondria-dependent cell apoptosis. Our findings shed light on the potential use of DMQ as a chemotherapeutic agent for CRC. 10.2174/1871520618666181106120718
    Novel quercetin derivatives: From redox properties to promising treatment of oxidative stress related diseases. Zizkova Petronela,Stefek Milan,Rackova Lucia,Prnova Marta,Horakova Lubica Chemico-biological interactions A set of O-substituted quercetin derivatives was prepared with the aim to optimize bioavailability and redox properties of quercetin, a known agent with multiple health beneficial effects. Electron-acceptor/-donor properties of the agents were evaluated theoretically by quantum chemical calculations and by experimental methods in cell-free model systems (2,2-diphenyl-1-picrylhydrazyl (DPPH) test, the ferric reducing ability of plasma (FRAP), peroxynitrite scavenging, protein-thiol oxidation) and in cellular systems of fibroblasts, microglials and cancer lines. The order of individual antioxidant effects varied dependently on the system used. In cellular systems, quercetin derivatives were shown to be better antioxidants compared to quercetin. Monochloropivaloylquercetin (CPQ), monoacetylferuloylquercetin (MAFQ) and chloronaphthoquinonequercetin (CHNQ) showed a prominent inhibitory effect on the key enzymes involved in diabetic complications, aldose reductase and α-glucosidase, suggesting their promising therapeutic application. In the cellular models of BHNF-3 fibroblasts, microglial cell line BV-2, colorectal cancer cell lines HCT-116 and HT-29, CHNQ and CPQ were studied for their cytotoxic, antiproliferative and antiinflammatory properties. In the rat model, CHNQ attenuated colon inflammation induced by acetic acid. In summary, our studies revealed CPQ and CHNQ as potential remedies of chronic age-related metabolic or inflammatory diseases, including diabetes and neurodegenerations. Furthermore, CHNQ represents a novel promising agent exerting its anticancer effect through induction of oxidative stress-dependent cell death. 10.1016/j.cbi.2017.01.019
    Taxifolin, a natural flavonoid interacts with cell cycle regulators causes cell cycle arrest and causes tumor regression by activating Wnt/ β -catenin signaling pathway. Razak Suhail,Afsar Tayyaba,Ullah Asad,Almajwal Ali,Alkholief Musaed,Alshamsan Aws,Jahan Sarwat BMC cancer BACKGROUND:New approaches for the prevention of colon cancer perseveres an essential necessity. Though, resistance to existing chemo-preventive drugs is moderately predominant in colon carcinogenesis. Taxifolin (dihydroquercetin) is a flavononol, have shown virile biological activities against few cancers. The current study was designed to investigate and equate antitumor activity of Taxifolin (TAX) in colorectal cancer cell lines and in HCT116 xenograft model in a comprehensive approach. METHODS:Two human colorectal cancer cell lines HCT116 and HT29, were used. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazoliumbromide (MMT) protocol was performed to elucidate the impact of TAX and β- catenin inhibitor (FH535) on the viability of HCT116 and HT29 cell lines. Apoptosis /cell cycle assay was performed. Data interpretation was done with a FACScan (Becton Dickinson, NJ). About 1 × 10 cells per sample were harvested. Histograms of DNA were analyzed with ModiFitLT software (verity Software House, ME, USA). Western blotting and RT-PCR were performed for protein and gene expression respectively in in vitro and in vivo. RESULTS:We found that TAX induced cytotoxicity in colorectal cells in a dose-dependent manner and time dependent approach. Further, our data validated that administration of TAX to human colorectal cancer HCT116 and HT29 cells resulted in cell growth arrest, variation in molecules controlling cell cycle operative in the G2 phase of the cell cycle and apoptosis in a concentration dependent approach. Further our results concluded that TAX administration decreases expression of β-catenin gene, AKT gene and Survivin gene and protein expression in in vitro and in vivo. CONCLUSION:Our findings proposed that targeting β-catenin gene may encourage the alterations of cell cycle and cell cycle regulators. Wnt/β-catenin signaling pathway possibly takes part in the genesis and progression of colorectal cancer cells through regulating cell cycle and the expression of cell cycle regulators. 10.1186/s12885-018-4959-4
    Chemopreventive effect of dietary polyphenols in colorectal cancer cell lines. Araújo João R,Gonçalves Pedro,Martel Fátima Nutrition research (New York, N.Y.) Colorectal cancer (CRC) is the second most fatal and the third most diagnosed type of cancer worldwide. Despite having multifactorial causes, most CRC cases are mainly determined by dietary factors. In recent years, a large number of studies have attributed a protective effect to polyphenols and foods containing these compounds (fruits and vegetables) against CRC. Indeed, polyphenols have been reported to interfere with cancer initiation, promotion, and progression, acting as chemopreventive agents. The aim of this review is to summarize the main chemopreventive properties of some polyphenols (quercetin, rutin, myricetin, chrysin, epigallocatechin-3-gallate, epicatechin, catechin, resveratrol, and xanthohumol) against CRC, observed in cell culture models. From the data reviewed in this article, it can be concluded that these compounds inhibit cell growth, by inducing cell cycle arrest and/or apoptosis; inhibit proliferation, angiogenesis, and/or metastasis; and exhibit anti-inflammatory and/or antioxidant effects. In turn, these effects involve multiple molecular and biochemical mechanisms of action, which are still not completely characterized. Thus, caution is mandatory when attempting to extrapolate the observations obtained in CRC cell line studies to humans. 10.1016/j.nutres.2011.01.006
    Preclinical colorectal cancer chemopreventive efficacy and p53-modulating activity of 3',4',5'-trimethoxyflavonol, a quercetin analogue. Howells Lynne M,Britton Robert G,Mazzoletti Marco,Greaves Peter,Broggini Massimo,Brown Karen,Steward William P,Gescher Andreas J,Sale Stewart Cancer prevention research (Philadelphia, Pa.) Some naturally occurring flavonols, exemplified by quercetin, seem to possess experimental cancer chemopreventive efficacy. Modulation of p53 is a mechanism thought to contribute to their activity. The hypothesis was tested that a synthetic flavonol, 3',4',5'-trimethoxyflavonol (TMFol), can interfere with tumor development and p53 expression in two models of colorectal carcinogenesis, Apc(Min) mice and human-derived HCT116 adenocarcinoma-bearing nude mice. Mice received TMFol with their diet (0.2%) from weaning to week 16 in the case of Apc(Min) or from either day 7 before ("TMFol early") or day 7 after ("TMFol late") tumor inoculation in HCT116 mice. The ability of TMFol to affect tumor proliferation or apoptosis, as reflected by staining for Ki-67 or cleaved caspase-3, respectively, was studied in HCT116 tumors. TMFol tumor levels were measured by high-performance liquid chromatography. Consumption of TMFol reduced small intestinal adenoma burden in Apc(Min) mice by 47%, compared with control mice (P < 0.002). The TMFol early regimen approximately halved HCT116 tumor size (P < 0.05), decreased tumor proliferation, and increased apoptosis, whereas the TMFol late regimen had no significant effect when compared with controls. In tumor tissues from mice, in which TMFol reduced tumor development, p53 expression was increased 3-fold in Apc(Min) and 1.5-fold in HCT116 tumor-bearing mice (P = 0.02). TMFol increased p53 also in cells derived from these tumors. TMFol was detected in HCT116 tumors, but levels did not correlate with tumor burden. TMFol was not mutagenic in the Ames test. The results suggest that chemical modification of the flavonol structure may generate safe and efficacious cancer chemopreventive agents. 10.1158/1940-6207.CAPR-09-0236
    Chemopreventive activity of plant flavonoid isorhamnetin in colorectal cancer is mediated by oncogenic Src and β-catenin. Saud Shakir M,Young Matthew R,Jones-Hall Yava L,Ileva Lilia,Evbuomwan Moses O,Wise Jennifer,Colburn Nancy H,Kim Young S,Bobe Gerd Cancer research Analysis of the Polyp Prevention Trial showed an association between an isorhamnetin-rich diet and a reduced risk of advanced adenoma recurrence; however, the mechanism behind the chemoprotective effects of isorhamnetin remains unclear. Here, we show that isorhamnetin prevents colorectal tumorigenesis of FVB/N mice treated with the chemical carcinogen azoxymethane and subsequently exposed to colonic irritant dextran sodium sulfate (DSS). Dietary isorhamnetin decreased mortality, tumor number, and tumor burden by 62%, 35%, and 59%, respectively. MRI, histopathology, and immunohistochemical analysis revealed that dietary isorhamnetin resolved the DSS-induced inflammatory response faster than the control diet. Isorhamnetin inhibited AOM/DSS-induced oncogenic c-Src activation and β-catenin nuclear translocation, while promoting the expression of C-terminal Src kinase (CSK), a negative regulator of Src family of tyrosine kinases. Similarly, in HT-29 colon cancer cells, isorhamnetin inhibited oncogenic Src activity and β-catenin nuclear translocation by inducing expression of csk, as verified by RNA interference knockdown of csk. Our observations suggest the chemoprotective effects of isorhamnetin in colon cancer are linked to its anti-inflammatory activities and its inhibition of oncogenic Src activity and consequential loss of nuclear β-catenin, activities that are dependent on CSK expression. 10.1158/0008-5472.CAN-13-0525
    Quercetrin from Toona sinensis leaves induces cell cycle arrest and apoptosis via enhancement of oxidative stress in human colorectal cancer SW620 cells. Zhang Yali,Guo Yucheng,Wang Mimi,Dong Huanhuan,Zhang Jingfang,Zhang Liyu Oncology reports Finding effective strategies against colorectal cancer (CRC) is still an emergent health problem. In the present study, we investigated the anticancer activity of quercetrin from Toona sinensis leaves (QTL) and explored the underlying mechanism in human CRC cell line SW620. The cells were treated with various concentrations of QTL and the cytotoxic effects of QTL were determined using the MTT assay. Apoptosis and cell cycle status were detected by flow cytometry. Reactive oxygen species (ROS) levels and mitochondrial membrane potential (∆Ψm) were assessed using DCF-DA and JC-1 fluorescence spectrophotometry, respectively. Western blot analysis was used to quantify the expression of apoptosis‑related proteins. RT-PCR was applied to determine the mRNA levels of glutathione peroxidase (GPx) and catalase (CAT). QTL exhibited growth inhibitory effects and caused cell cycle arrest in the G2/M phase, which was accompanied by increased expression of p53 and p21 proteins. QTL promoted apoptosis which was consistent with the upregulated expression of Bax, cytochrome c, caspase-9, Apaf-1 and caspase-3. In addition, QTL induced the loss of mitochondrial membrane potential and triggered ROS generation, as revealed by the downregulated mRNA expression and enzymatic activity of GPx and CAT. Furthermore, both N‑acetyl cysteine (NAC) and GSH attenuated the QTL-induced growth inhibition observed in SW620 cells along with the increase of ROS levels. These findings revealed that QTL inhibited the growth of CRC cells and facilitated apoptosis by enhancing oxidative stress. QTL may therefore have potential for use in CRC chemotherapy. 10.3892/or.2017.6042