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      Long Term Exposure to Polyphenols of Artichoke ( Cynara scolymus L.) Exerts Induction of Senescence Driven Growth Arrest in the MDA-MB231 Human Breast Cancer Cell Line

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          Abstract

          Polyphenolic extracts from the edible part of artichoke ( Cynara scolymus L.) have been shown to be potential chemopreventive and anticancer dietary compounds. High doses of polyphenolic extracts (AEs) induce apoptosis and decrease the invasive potential of the human breast cancer cell line, MDA-MB231. However, the molecular mechanism underlying AEs antiproliferative effects is not completely understood. We demonstrate that chronic and low doses of AEs treatment at sublethal concentrations suppress human breast cancer cell growth via a caspases-independent mechanism. Furthermore, AEs exposure induces a significant increase of senescence-associated β-galactosidase (SA- β-gal) staining and upregulation of tumour suppressor genes, p16 INK4a and p21 Cip1/Waf1 in MDA-MB231 cells. AEs treatment leads to epigenetic alterations in cancer cells, modulating DNA hypomethylation and lysine acetylation levels in total proteins. Cell growth arrest correlates with increased reactive oxygen species (ROS) production in AEs treated breast cancer cells. Inhibition of ROS generation by N-acetylcysteine (NAC) attenuates the antiproliferative effect. These findings demonstrate that chronic AEs treatment inhibits breast cancer cell growth via the induction of premature senescence through epigenetic and ROS-mediated mechanisms. Our results suggest that artichoke polyphenols could be a promising dietary tool either in cancer chemoprevention or/and in cancer treatment as a nonconventional, adjuvant therapy.

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          Most cited references60

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          Therapy-induced senescence in cancer.

          Cellular senescence is a response to nonlethal stress that results in persistent cytostasis with a distinct morphological and biochemical phenotype. The senescence phenotype, detected in tumors through the expression of mRNA and protein markers, can be generated in cancer cells lacking functional p53 and retinoblastoma protein. Current research suggests that therapy-induced senescence (TIS) represents a novel functional target that may improve cancer therapy. TIS can be induced in immortal and transformed cancer cells by selected anticancer compounds or radiation, and accumulating data indicate that TIS may produce reduced toxicity-related side effects and increased tumor-specific immune activity. This review examines the current status of TIS-regulated mechanisms, agents, and senescence biomarkers with the goal of encouraging further development of this approach to cancer therapy. Remaining hurdles include the lack of efficient senescence-inducing agents and incomplete biological data on tumor response. The identification of additional compounds and other targeted approaches to senescence induction will further the development of TIS in the clinical treatment of cancer.
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            Tumor cell senescence in cancer treatment.

            Cell senescence is broadly defined as the physiological program of terminal growth arrest, which can be triggered by alterations of telomeres or by different forms of stress. Neoplastic transformation involves events that inhibit the program of senescence, and tumor cells were believed until recently to have lost the ability to senesce. It has now become apparent, however, that tumor cells can be readily induced to undergo senescence by genetic manipulations or by treatment with chemotherapeutic drugs, radiation, or differentiating agents. Treatment-induced senescence, which has both similarities with, and differences from, replicative senescence of normal cells, was shown to be one of the key determinants of tumor response to therapy in vitro and in vivo. Although senescent cells do not proliferate, they remain metabolically active and produce secreted proteins with both tumor-suppressing and tumor-promoting activities. Expression of tumor-promoting factors by senescent cells is mediated, at least in part, by senescence-associated cyclin-dependent kinase inhibitors such as p21(Waf1/Cip1/Sdi1). Clinical and preclinical studies indicate that expression of different biological classes of senescence-associated growth-regulatory genes in tumor cells has significant prognostic implications. Elucidation of the genes and regulatory mechanisms that determine different aspects of tumor senescence makes it possible to design new therapeutic approaches to improving the efficacy and to decreasing the side effects of cancer therapy.
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              A two-way street: reciprocal regulation of metabolism and signalling.

              It is becoming increasingly clear that cellular signalling and metabolism are not just separate entities but rather are tightly linked. Although nutrient metabolism is known to be regulated by signal transduction, an emerging paradigm is that signalling and transcriptional networks can be modulated by nutrient-sensitive protein modifications, such as acetylation and glycosylation, which depend on the availability of acetyl-CoA and sugar donors such as UDP-N-acetylglucosamine (UDP-GlcNAc), respectively. The integration of metabolic and signalling cues allows cells to modulate activities such as metabolism, cell survival and proliferation according to their intracellular metabolic resources.
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                Author and article information

                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi Publishing Corporation
                1942-0900
                1942-0994
                2015
                9 June 2015
                : 2015
                : 363827
                Affiliations
                1Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
                2CNR, Institute of Sciences of Food Production (ISPA), Via Amendola 122/O, 70126 Bari, Italy
                Author notes
                *Stefania Miccadei: miccadei@ 123456ifo.it

                Academic Editor: Tullia Maraldi

                Article
                10.1155/2015/363827
                4477242
                26180585
                aeef655f-7995-4a6b-b763-d7693759413e
                Copyright © 2015 Anna Maria Mileo et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 8 July 2014
                : 8 September 2014
                Categories
                Research Article

                Molecular medicine
                Molecular medicine

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