In vivo relevant mixed urolithins and ellagic acid inhibit phenotypic and molecular colon cancer stem cell features: A new potentiality for ellagitannin metabolites against cancer

Núñez‐Sánchez, María Ángeles; Karmokar, Ankur; González‐Sarrías, Antonio; Garcı́a-Villalba, Rocío; Tomás-Barberán, Francisco A.; Garcı́a-Conesa, María Teresa; Brown, Karen; Espı́n, Juan Carlos

doi:10.1016/j.fct.2016.03.011

Cited by 59 publications

(29 citation statements)

References 52 publications

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“…Hence, we next sought to determine whether natural extracts and ITCs were able to target the CSC-like phenotype and evade cell chemoresistance by modulation of ALDH1 activity even at doses bellow extracts’ EC 50 values obtained in antiproliferative assays, as described in other studies [64,65]. More precisely, the maximum dose tested for each extract and respective ITC was an approximated value of half the extract’s EC 50 value (30 µM for SFN/broccoli extract and 60 µM PEITC/watercress extract).…”

Section: Resultsmentioning

confidence: 99%

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Pereira

Silva²,

Duarte³

et al. 2017

Nutrients

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Colorectal cancer (CRC) recurrence is often attributable to circulating tumor cells and/or cancer stem cells (CSCs) that resist to conventional therapies and foster tumor progression. Isothiocyanates (ITCs) derived from Brassicaceae vegetables have demonstrated anticancer effects in CRC, however little is known about their effect in CSCs and tumor initiation properties. Here we examined the effect of ITCs-enriched Brassicaceae extracts derived from watercress and broccoli in cell proliferation, CSC phenotype and metastasis using a previously developed three-dimensional HT29 cell model with CSC-like traits. Both extracts were phytochemically characterized and their antiproliferative effect in HT29 monolayers was explored. Next, we performed cell proliferation assays and flow cytometry analysis in HT29 spheroids treated with watercress and broccoli extracts and respective main ITCs, phenethyl isothiocyanate (PEITC) and sulforaphane (SFN). Soft agar assays and relative quantitative expression analysis of stemness markers and Wnt/β-catenin signaling players were performed to evaluate the effect of these phytochemicals in stemness and metastasis. Our results showed that both Brassicaceae extracts and ITCs exert antiproliferative effects in HT29 spheroids, arresting cell cycle at G2/M, possibly due to ITC-induced DNA damage. Colony formation and expression of LGR5 and CD133 cancer stemness markers were significantly reduced. Only watercress extract and PEITC decreased ALDH1 activity in a dose-dependent manner, as well as β-catenin expression. Our research provides new insights on CRC therapy using ITC-enriched Brassicaceae extracts, specially watercress extract, to target CSCs and circulating tumor cells by impairing cell proliferation, ALDH1-mediated chemo-resistance, anoikis evasion, self-renewal and metastatic potential.

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Section: Resultsmentioning

confidence: 99%

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Pereira

Silva²,

Duarte³

et al. 2017

Nutrients

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“…27,54 Also phenolic acids and flavonoids present in nuts or urolithins as colonic metabolites could contribute to the growth inhibitory effects. 48,55 The anti-proliferative effects of nut FS could be the result of apoptotic processes. The present study demonstrates that all nut FS significantly enhanced the percentage of early apoptotic cells as well as caspase 3 activity as a marker of advanced apoptosis in LT97 cells after 24 h treatment.…”

Section: Discussionmentioning

confidence: 99%

Chemopreventive potential of in vitro fermented nuts in LT97 colon adenoma and primary epithelial colon cells

Schlörmann

Lamberty

Lorkowski³

et al. 2017

Molecular Carcinogenesis

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Due to their beneficial nutritional profile the consumption of nuts contributes to a healthy diet and might reduce colon cancer risk. To get closer insights into potential mechanisms, the chemopreventive potential of different in vitro fermented nut varieties regarding the modulation of genes involved in detoxification (CAT, SOD2, GSTP1, GPx1) and cell cycle (p21, cyclin D2) as well as proliferation and apoptosis was examined in LT97 colon adenoma and primary epithelial colon cells. Fermentation supernatants (FS) of nuts significantly induced mRNA expression of CAT (up to 4.0-fold), SOD2 (up to 2.5-fold), and GSTP1 (up to 2.3-fold), while GPx1 expression was significantly reduced by all nut FS (0.8 fold on average). Levels of p21 mRNA were significantly enhanced (up to 2.6-fold), whereas all nut FS significantly decreased cyclin D2 expression (0.4-fold on average). In primary epithelial cells, expression of CAT (up to 3.5-fold), GSTP1 (up to 3.0-fold), and GPx1 (up to 3.9-fold) was increased, whereas p21 and cyclin D2 levels were not influenced. Nut FS significantly inhibited growth of LT97 cells and increased levels of early apoptotic cells (8.4% on average) and caspase 3 activity (4.6-fold on average), whereas caspase 3 activity was not modulated in primary colon cells. The differential modulation of genes involved in detoxification and cell cycle together with an inhibition of proliferation and induction of apoptosis in adenoma cells might contribute to chemopreventive effects of nuts regarding colon cancer.

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“…Using colon cancer stem cells, Núñez-Sánchez et al [182] evaluated the effect of a mixture of ellagic acid (5 %) and the gut microbiota-derived urolithins A (85 %) and C (10 %) detected in human colon tissues after intake of products with a high amount of ellagitannin, such as pomegranates and walnuts. The mixture not only inhibited aldehyde dehydrogenase activity, but also decreased the number (26.3 ± 3.8 %) and size (23.7 ± 7.4 %) of colonospheres in primary tumor cells from a patient with colorectal cancer, providing evidence for its potential role against colon cancer chemoresistance and relapse.…”

Section: Cytotoxic Antitumor and Anticancer Effects Of Ellagic Acidmentioning

confidence: 99%

A Pharmacological Update of Ellagic Acid

et al. 2018

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Ellagic acid is a common metabolite present in many medicinal plants and vegetables. It is present either in free form or as part of more complex molecules (ellagitannins), which can be metabolized to liberate ellagic acid and several of its metabolites, including urolithins. While ellagic acidʼs antioxidant properties are doubtless responsible for many of its pharmacological activities, other mechanisms have also been implicated in its various effects, including its ability to reduce the lipidemic profile and lipid metabolism, alter pro-inflammatory mediators (tumor necrosis factor-α, interleukin-1β, interleukin-6), and decrease the activity of nuclear factor-κB while increasing nuclear factor erythroid 2-related factor 2 expression. These events play an important role in ellagic acidʼs anti-atherogenic, anti-inflammatory, and neuroprotective effects. Several of these activities, together with the effect of ellagic acid on insulin, glycogen, phosphatases, aldose reductase, sorbitol accumulation, advanced glycation end-product formation, and resistin secretion, may explain its effects on metabolic syndrome and diabetes. In addition, results from recent research have increased the interest in ellagic acid, both as a potential protective agent of the liver and skin and as a potential anticancer agent, due to the specific mechanisms affecting cell proliferation, apoptosis, DNA damage, and angiogenesis and its aforementioned anti-inflammatory properties. Taken together, these effects make ellagic acid a highly interesting compound that may contribute to different aspects of health; however, more studies are needed, especially on the compoundʼs pharmacokinetic profile. In this review, we selected papers published from 2005 to the present.

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In vivo relevant mixed urolithins and ellagic acid inhibit phenotypic and molecular colon cancer stem cell features: A new potentiality for ellagitannin metabolites against cancer

Cited by 59 publications

References 52 publications

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Chemopreventive potential of in vitro fermented nuts in LT97 colon adenoma and primary epithelial colon cells

A Pharmacological Update of Ellagic Acid

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