Dataset Information

Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis.

ABSTRACT: We have previously shown that the grape bioactive compound resveratrol (RSV) potentiates grape seed extract (GSE)-induced colon cancer cell apoptosis at physiologically relevant concentrations. However, RSV-GSE combination efficacy against colon cancer stem cells (CSCs), which play a key role in chemotherapy and radiation resistance, is not known.We tested the anti-cancer efficacy of the RSV-GSE against colon CSCs using isolated human colon CSCs in vitro and an azoxymethane-induced mouse model of colon carcinogenesis in vivo.RSV-GSE suppressed tumor incidence similar to sulindac, without any gastrointestinal toxicity. Additionally, RSV-GSE treatment reduced the number of crypts containing cells with nuclear ?-catenin (an indicator of colon CSCs) via induction of apoptosis. In vitro, RSV-GSE suppressed - proliferation, sphere formation, nuclear translocation of ?-catenin (a critical regulator of CSC proliferation) similar to sulindac in isolated human colon CSCs. RSV-GSE, but not sulindac, suppressed downstream protein levels of Wnt/?-catenin pathway, c-Myc and cyclin D1. RSV-GSE also induced mitochondrial-mediated apoptosis in colon CSCs characterized by elevated p53, Bax/Bcl-2 ratio and cleaved PARP. Furthermore, shRNA-mediated knockdown of p53, a tumor suppressor gene, in colon CSCs did not alter efficacy of RSV-GSE.The suppression of Wnt/?-catenin signaling and elevated mitochondrial-mediated apoptosis in colon CSCs support potential clinical testing/application of grape bioactives for colon cancer prevention and/or therapy.

SUBMITTER: Reddivari L

PROVIDER: S-EPMC4977641 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis.

Reddivari Lavanya L Charepalli Venkata V Radhakrishnan Sridhar S Vadde Ramakrishna R Elias Ryan J RJ Lambert Joshua D JD Vanamala Jairam K P JK

BMC complementary and alternative medicine 20160809

<h4>Background</h4>We have previously shown that the grape bioactive compound resveratrol (RSV) potentiates grape seed extract (GSE)-induced colon cancer cell apoptosis at physiologically relevant concentrations. However, RSV-GSE combination efficacy against colon cancer stem cells (CSCs), which play a key role in chemotherapy and radiation resistance, is not known.<h4>Methods</h4>We tested the anti-cancer efficacy of the RSV-GSE against colon CSCs using isolated human colon CSCs in vitro and an ...[more]

PMID: 27506388

Similar Datasets

Project description:Epidemiological evidence suggests that a diet abundant in fruits and vegetables may protect against colon cancer. Bioactive compounds, including flavonoids and limonoids, have been shown to possess antiproliferative and antitumorigenic effects in various cancer models. This experiment investigated the effects of four citrus flavonoids and one limonoid mixture at the promotion stage of chemically induced colon cancer in rats. Male Sprague-Dawley rats (n = 10 rats/group) were randomly allocated to one of six diets formulated to contain 0.1% apigenin, 0.02% naringenin, 0.1% hesperidin, 0.01% nobiletin, 0.035% limonin glucoside/obacunone glucoside mixture or a control diet (0% flavonoid/limonoid). Rats received experimental diets for 10 weeks and were injected with azoxymethane (15 mg/kg) at weeks 3 and 4. Excised colons were evaluated for aberrant crypt foci (ACF) formation, colonocyte proliferation (proliferating cell nuclear antigen assay), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling assay) and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) (immunoblotting). When compared with the control diet, apigenin lowered the number of high multiplicity ACF (HMACF >4 aberrant crypts/focus) by 57% (P < 0.05), while naringenin lowered both the number of HMACF by 51% (P < 0.05) and the proliferative index by 32% (P < 0.05). Both apigenin and naringenin increased apoptosis of luminal surface colonocytes (78% and 97%, respectively; P < 0.05) when compared with the control diet. Hesperidin, nobiletin and the limonin glucoside/obacunone glucoside mixture did not affect these variables. The colonic mucosal protein levels of iNOS or COX-2 were not different among the six diet groups. The ability of dietary apigenin and naringenin to reduce HMACF, lower proliferation (naringenin only) and increase apoptosis may contribute toward colon cancer prevention. However, these effects were not due to mitigation of iNOS and COX-2 protein levels at the ACF stage of colon cancer.

Project description:N-nitroso compounds (NOC) are genotoxic compounds and animal carcinogens, and may play a role in human cancer development. Since the gastro-intestinal tract is an important route of exposure, we hypothesize that NOC exposure targets genetic processes relevant in colon carcinogenesis. To investigate this, we analysed the transcriptomic effects of genotoxic concentrations of two nitrosamides, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 1ÂµM) and N-methyl-N-nitrosurea (MNU, 1mM), and four nitrosamines, N-nitrosodiethylamine (NDEA, 50mM), N-nitrosodimethylamine (NDMA, 100mM), N-nitrosopiperidine (NPIP, 40mM), and N-nitrosopyrrolidine (NPYR, 100mM), in the human colon carcinoma cell line Caco-2. Gene Ontology gene group, consensus motif gene group and biological pathway analysis revealed that nitrosamides had little effect on gene expression after 24 hours of exposure, whereas nitrosamines had a strong impact on the transcriptomic profile. Analyses showed modifications of cell cycle regulation and apoptosis pathways for nitrosamines which was supported by flow cytometric analysis. We found additional modifications in gene groups and pathways of oxidative stress and inflammation, which suggest an increase in oxidative stress and pro-inflammatory immune response upon nitrosamine exposure, although less distinct for NDMA. Furthermore, NDEA, NPIP and NPYR most strongly affected several developmental motif gene groups and pathways, which may influence developmental processes. Many of these pathways and gene groups are implicated in the carcinogenic process and their modulation by nitrosamine exposure may therefore influence the development of colon cancer. In summary, our study has identified pathway modifications in human colon cells which may be associated with cancer risk of nitrosamine exposure in the human colon. Keywords: Comparison of genome-wide gene expression between different conditions The study investigated differential gene expression in Caco-2 cell line mRNA following 24 hours of exposure to six different N-nitroso compounds. Four biological replicates per sample compound. One compound per array, hybridized against vehicle control. Dye-swap between biological replicates 1 and 2, and 3 and 4.

Dataset Information

Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis.

Publications

Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets