Ellagic acid, a natural polyphenolic compound, induces apoptosis and potentiates retinoic acid-induced differentiation of human leukemia HL-60 cells

ArticleinInternational journal of hematology 92(1):136-43 · July 2010with32 Reads
DOI: 10.1007/s12185-010-0627-4 · Source: PubMed
All-trans retinoic acid (ATRA) is a standard drug used for differentiation therapy in acute promyelocytic leukemia. To potentiate this therapy, we examined the effect of ellagic acid (EA), a natural polyphenolic compound with antiproliferative and antioxidant properties, on the growth and differentiation of HL-60 acute myeloid leukemia cells. EA was found to induce apoptosis, which was blocked by pan-caspase inhibitor, Z-VAD-FMK. EA activated the caspase-3 pathway and enhanced the expressions of myeloid differentiation markers (CD11b, MRP-14 protein, granulocytic morphology) induced by ATRA treatment. These results indicate that EA is a potent apoptosis inducer and also effectively potentiates ATRA-induced myeloid differentiation of HL-60 cells.
    • "The milder effect of fresh juice could be attributed to the fact that flavonoids are presumably bound to sugar moieties, whereas after fermentation they are free. Interestingly, ellagic acid (25 í µí¼‡M) enhanced retinoic acid-induced differentiation of promyelocytic leukemic cells towards granulocytic phenotype [122]. Thus, the association of retinoic acid with ellagic acid might be a promising strategy to reduce the therapeutic dosage of retinoic acid and its cardiorespiratory toxicity [124]. "
    [Show abstract] [Hide abstract] ABSTRACT: Cancer is the second leading cause of death and is becoming the leading one in old age. Vegetable and fruit consumption is inversely associated with cancer incidence and mortality. Currently, interest in a number of fruits high in polyphenols has been raised due to their reported chemopreventive and/or chemotherapeutic potential. Pomegranate has been shown to exert anticancer activity, which is generally attributed to its high content of polyphenols. This review provides a comprehensive analysis of known targets and mechanisms along with a critical evaluation of pomegranate polyphenols as future anticancer agents. Pomegranate evokes antiproliferative, anti-invasive, and antimetastatic effects, induces apoptosis through the modulation of Bcl-2 proteins, upregulates p21 and p27, and downregulates cyclin-cdk network. Furthermore, pomegranate blocks the activation of inflammatory pathways including, but not limited to, the NF-κB pathway. The strongest evidence for its anticancer activity comes from studies on prostate cancer. Accordingly, some exploratory clinical studies investigating pomegranate found a trend of efficacy in increasing prostate-specific antigen doubling time in patients with prostate cancer. However, the genotoxicity reported for pomegranate raised certain concerns over its safety and an accurate assessment of the risk/benefit should be performed before suggesting the use of pomegranate or its polyphenols for cancer-related therapeutic purposes.
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    • "In contrast, four out of nine EA combinations and eight out of nine RA combinations applied showed synergism according to the equation of Chou and Talalay (1984) (Tables 4 and 5). 2010 ), to induce cell cycle arrest and apoptosis, and to act as cancer chemopreventive agents in a multitude of preclinical and animal studies (Hagiwara et al. 2010; Heber 2008; Ngo et al. 2011; Petersen and Simmonds 2003; Singh et al. 2011; Viladomiu et al. 2013; Wu and Wang 2012). In this study, we report for the first time the effects of these natural compounds on ribonucleotide reductase (RR) metabolism in human HL-60 promyelocytic leukemia cells. "
    [Show abstract] [Hide abstract] ABSTRACT: Epigallocatechin gallate (EGCG), ellagic acid (EA) and rosmarinic acid (RA) are natural polyphenols exerting cancer chemopreventive effects. Ribonucleotide reductase (RR; EC converts ribonucleoside diphosphates into deoxyribonucleoside diphosphates being essential for DNA replication, which is why the enzyme is considered an excellent target for anticancer therapy. EGCG, EA, and RA dose-dependently inhibited the growth of human HL-60 promyelocytic leukemia cells, exerted strong free radical scavenging potential, and significantly imbalanced nuclear deoxyribonucleoside triphosphate (dNTP) concentrations without distinctly affecting the protein levels of RR subunits (R1, R2, p53R2). Incorporation of (14)C-cytidine into nascent DNA of tumor cells was also significantly lowered, being equivalent to an inhibition of DNA synthesis. Consequently, treatment with EGCG and RA attenuated cells in the G0/G1 phase of the cell cycle, finally resulting in a pronounced induction of apoptosis. Sequential combination of EA and RA with the first-line antileukemic agent arabinofuranosylcytosine (AraC) synergistically potentiated the antiproliferative effect of AraC, whereas EGCG plus AraC yielded additive effects. Taken together, we show for the first time that EGCG, EA, and RA perturbed dNTP levels and inhibited cell proliferation in human HL-60 promyelocytic leukemia cells, with EGCG and RA causing a pronounced induction of apoptosis. Due to these effects and synergism with AraC, these food ingredients deserve further preclinical and in vivo testing as inhibitors of leukemic cell proliferation. Copyright © 2014 Elsevier GmbH. All rights reserved.
    Full-text · Article · Jan 2015
    • "Ellagic acid (EA) and gallic acid (GA) are two important phenolic compounds present in many medicinal plants. They show a large variety of biological activities including antioxidant, antimicrobial and anticancer activity (Faried et al., 2007; Wansi et al., 2010; Hagiwara et al., 2010). EA and GA can exist in plant material in free form but the main sources of these compounds are hydrolyzable tannins (ellagitannins and gallotannins), which upon hydrolysis release a sugar and a respective acid moiety (Haslam, 2007; Serrano et al., 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: Hydrolyzable tannins and products of their hydrolysis, ellagic acid (EA) and gallic acid (GA), are important constituents of many medicinal plants and exhibit various biological activities. Geum rivale and G. urbanum are traditional herbal remedies rich in tannin compounds. The aim of the study was to quantitate free and total EA and GA in aerial and underground parts of G. rivale and G. urbanum. After optimization of extraction, both compounds were quantitated by reversed phase HPLC (RP-HPLC). EA was more abundant than GA in the investigated material, and underground parts of G. rivale were the richest source of total EA and GA.
    Full-text · Article · Jan 2015
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