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      Telomerase Inhibitors from Natural Products and Their Anticancer Potential

      review-article
      , *
      International Journal of Molecular Sciences
      MDPI
      telomere, telomerase inhibitors, natural products, anticancer

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          Abstract

          Telomeres and telomerase are nowadays exploring traits on targets for anticancer therapy. Telomerase is a unique reverse transcriptase enzyme, considered as a primary factor in almost all cancer cells, which is mainly responsible to regulate the telomere length. Hence, telomerase ensures the indefinite cell proliferation during malignancy—a hallmark of cancer—and this distinctive feature has provided telomerase as the preferred target for drug development in cancer therapy. Deactivation of telomerase and telomere destabilization by natural products provides an opening to succeed new targets for cancer therapy. This review aims to provide a fundamental knowledge for research on telomere, working regulation of telomerase and its various binding proteins to inhibit the telomere/telomerase complex. In addition, the review summarizes the inhibitors of the enzyme catalytic subunit and RNA component, natural products that target telomeres, and suppression of transcriptional and post-transcriptional levels. This extensive understanding of telomerase biology will provide indispensable information for enhancing the efficiency of rational anti-cancer drug design.

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          Most cited references227

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          How telomeres solve the end-protection problem.

          The ends of eukaryotic chromosomes have the potential to be mistaken for damaged or broken DNA and must therefore be protected from cellular DNA damage response pathways. Otherwise, cells might permanently arrest in the cell cycle, and attempts to "repair" the chromosome ends would have devastating consequences for genome integrity. This end-protection problem is solved by protein-DNA complexes called telomeres. Studies of mammalian cells have recently uncovered the mechanism by which telomeres disguise the chromosome ends. Comparison to unicellular eukaryotes reveals key differences in the DNA damage response systems that inadvertently threaten chromosome ends. Telomeres appear to be tailored to these variations, explaining their variable structure and composition.
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            Epigallocatechin-3-gallate (EGCG): chemical and biomedical perspectives.

            The compound (-)-epigallocatechin-3-gallate (EGCG) is the major catechin found in green tea [Camellia sinensis L. Ktze. (Theaceae)]. This polyphenolic compound and several related catechins are believed to be responsible for the health benefits associated with the consumption of green tea. The potential health benefits ascribed to green tea and EGCG include antioxidant effects, cancer chemoprevention, improving cardiovascular health, enhancing weight loss, protecting the skin from the damage caused by ionizing radiation, and others. The compound EGCG has been shown to regulate dozens of disease-specific molecular targets. Many of these molecular targets are only affected by concentrations of EGCG that are far above the levels achieved by either drinking green tea or consuming moderate doses of green tea extract-based dietary supplements. In spite of this, well-designed double-blinded controlled clinical studies have recently demonstrated the efficacy of green tea extracts and purified EGCG products in patients. Therefore, this review highlights results from what the authors believe to be some of the most clinically significant recent studies and describes current developments in the stereoselective total synthesis of EGCG.
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              Quercetin and Cancer Chemoprevention

              Several molecules present in the diet, including flavonoids, can inhibit the growth of cancer cells with an ability to act as “chemopreventers”. Their cancer-preventive effects have been attributed to various mechanisms, including the induction of cell-cycle arrest and/or apoptosis as well as the antioxidant functions. The antioxidant activity of chemopreventers has recently received a great interest, essentially because oxidative stress participates in the initiation and progression of different pathological conditions, including cancer. Since antioxidants are capable of preventing oxidative damage, the wide use of natural food-derived antioxidants is receiving greater attention as potential anti-carcinogens. Among flavonoids, quercetin (Qu) is considered an excellent free-radical scavenging antioxidant, even if such an activity strongly depends on the intracellular availability of reduced glutathione. Apart from antioxidant activity, Qu also exerts a direct, pro-apoptotic effect in tumor cells, and can indeed block the growth of several human cancer cell lines at different phases of the cell cycle. Both these effects have been documented in a wide variety of cellular models as well as in animal models. The high toxicity exerted by Qu on cancer cells perfectly matches with the almost total absence of any damages for normal, non-transformed cells. In this review we discuss the molecular mechanisms that are based on the biological effects of Qu, and their relevance for human health.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                21 December 2017
                January 2018
                : 19
                : 1
                : 13
                Affiliations
                Food Science and Technology Program, Beijing Normal University–Hong Kong Baptist University United International College, Zhuhai 519087, China; kumarganesan@ 123456uic.edu.hk
                Author notes
                [* ]Correspondence: baojunxu@ 123456uic.edu.hk ; Tel.: +86-756-3620-636; Fax: +86-756-3620-882
                Author information
                https://orcid.org/0000-0002-3198-6066
                https://orcid.org/0000-0003-0739-3735
                Article
                ijms-19-00013
                10.3390/ijms19010013
                5795965
                29267203
                9de0ad78-2903-4376-ae79-d31ad845cdd9
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 23 November 2017
                : 19 December 2017
                Categories
                Review

                Molecular biology
                telomere,telomerase inhibitors,natural products,anticancer
                Molecular biology
                telomere, telomerase inhibitors, natural products, anticancer

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