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      Ruthenation of Non‐stacked Guanines in DNA G‐Quadruplex Structures: Enhancement of c‐MYC Expression

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          Abstract

          Guanine quadruplexes (GQs) are compact four‐stranded DNA structures that play a key role in the control of a variety of biological processes, including gene transcription. Bulky ruthenium complexes featuring a bipyridine, a terpyridine, and one exchangeable ligand ([Ru(terpy)(bpy)X] n+ ) are able to metalate exposed guanines present in the GQ of the c‐MYC promoter region that are not involved in quadruplex base pairing. qRT‐PCR and western‐blot experiments indicated that the complexes promote a remarkable increase in the expression of this oncogene. We also show that exchangeable thioether ligands (X=RSR′, Met) allow regulation of the metalating activity of the complex with visible light.

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          c-Myc proteolysis by the ubiquitin-proteasome pathway: stabilization of c-Myc in Burkitt's lymphoma cells.

          M Gregory, S Hann (2000)
          The c-Myc oncoprotein is a transcription factor which is a critical regulator of cellular proliferation. Deregulated expression of c-Myc is associated with many human cancers, including Burkitt's lymphoma. The c-Myc protein is normally degraded very rapidly with a half-life of 20 to 30 min. Here we demonstrate that proteolysis of c-Myc in vivo is mediated by the ubiquitin-proteasome pathway. Inhibition of proteasome activity blocks c-Myc degradation, and c-Myc is a substrate for ubiquitination in vivo. Furthermore, an increase in c-Myc stability occurs in mitotic cells and is associated with inhibited c-Myc ubiquitination. Deletion analysis was used to identify regions of the c-Myc protein which are required for rapid proteolysis. We found that a centrally located PEST sequence, amino acids 226 to 270, is necessary for rapid c-Myc degradation, but not for ubiquitination. Also, N-terminal sequences, located within the first 158 amino acids of c-Myc, are necessary for both efficient c-Myc ubiquitination and subsequent degradation. We found that c-Myc is significantly stabilized (two- to sixfold) in many Burkitt's lymphoma-derived cell lines, suggesting that aberrant c-Myc proteolysis may play a role in the pathogenesis of Burkitt's lymphoma. Finally, mutation of Thr-58, a major phosphorylation site in c-Myc and a mutational hot spot in Burkitt's lymphoma, increases c-Myc stability; however, mutation of c-Myc is not essential for stabilization in Burkitt's lymphoma cells.
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            Recent developments in ruthenium anticancer drugs.

            Aviva Levina, P A Lay, A. N. Mitra (2009)
            Interest in Ru anticancer drugs has been growing rapidly since NAMI-A ((ImH(+))[Ru(III)Cl(4)(Im)(S-dmso)], where Im = imidazole and S-dmso = S-bound dimethylsulfoxide) or KP1019 ((IndH(+))[Ru(III)Cl(4)(Ind)(2)], where Ind = indazole) have successfully completed phase I clinical trials and an array of other Ru complexes have shown promise for future development. Herein, the recent literature is reviewed critically to ascertain likely mechanisms of action of Ru-based anticancer drugs, with the emphasis on their reactions with biological media. The most likely interactions of Ru complexes are with: (i) albumin and transferrin in blood plasma, the former serving as a Ru depot, and the latter possibly providing active transport of Ru into cells; (ii) collagens of the extracellular matrix and actins on the cell surface, which are likely to be involved in the specific anti-metastatic action of Ru complexes; (iii) regulatory enzymes within the cell membrane and/or in the cytoplasm; and (iv) DNA in the cell nucleus. Some types of Ru complexes can also promote the intracellular formation of free radical species, either through irradiation (photodynamic therapy), or through reactions with cellular reductants. The metabolic pathways involve competition among reduction, aquation, and hydrolysis in the extracellular medium; binding to transport proteins, the extracellular matrix, and cell-surface biomolecules; and diffusion into cells; with the extent to which individual drugs participate in various steps along these pathways being crucial factors in determining whether they are mainly anti-metastatic or cytotoxic. This diversity of modes of action of Ru anticancer drugs is also likely to enhance their anticancer activities and to reduce the potential for them to develop tumour resistance. New approaches to metabolic studies, such as X-ray absorption spectroscopy and X-ray fluorescence microscopy, are required to provide further mechanistic insights, which could lead to the rational design of improved Ru anticancer drugs.
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              New metal complexes as potential therapeutics.

              Christiana Xin Zhang, Stephen Lippard (2003)
              The many activities of metal ions in biology have stimulated the development of metal-based therapeutics. Cisplatin, as one of the leading metal-based drugs, is widely used in treatment of cancer, being especially effective against genitourinary tumors such as testicular. Significant side effects and drug resistance, however, have limited its clinical applications. Biological carriers conjugated to cisplatin analogs have improved specificity for tumor tissue, thereby reducing side effects and drug resistance. Platinum complexes with distinctively different DNA binding modes from that of cisplatin also exhibit promising pharmacological properties. Ruthenium and gold complexes with antitumor activity have also evolved. Other metal-based chemotherapeutic compounds have been investigated for potential medicinal applications, including superoxide dismutase mimics and metal-based NO donors/scavengers. These compounds have the potential to modulate the biological properties of superoxide anion and nitric oxide.
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                Author and article information

                Contributors
                Dr. M. Eugenio Vázquez:
                ORCID: http://orcid.org/0000-0001-7500-985X
                eugenio.vazquez@usc.es
                Prof. José L. Mascareñas:
                ORCID: http://orcid.org/0000-0002-7789-700X
                joseluis.mascarenas@usc.es
                Journal
                Journal ID (nlm-ta): Angew Chem Int Ed Engl
                Journal ID (iso-abbrev): Angew. Chem. Int. Ed. Engl
                Journal ID (doi): 10.1002/(ISSN)1521-3773
                Journal ID (publisher-id): ANIE
                Title: Angewandte Chemie (International Ed. in English)
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1433-7851
                ISSN (Electronic): 1521-3773
                Publication date (Electronic): 17 November 2016
                Publication date (Print): 12 December 2016
                Volume: 55
                Issue: 50 ( doiID: 10.1002/anie.v55.50 )
                Pages: 15615-15618
                Affiliations
                [ 1 ] Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), and Departamento de Química Orgánica Universidade de Santiago de Compostela 15782 Santiago de CompostelaSpain
                Author information
                http://orcid.org/0000-0001-7500-985X
                http://orcid.org/0000-0002-7789-700X
                Article
                Publisher ID: ANIE201607965
                DOI: 10.1002/anie.201607965
                PMC ID: 5299515
                PubMed ID: 27860057
                SO-VID: ec686955-7fb7-46ef-914f-af70dc3e10ac
                Copyright © © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 17 August 2016
                Date revision received : 29 September 2016
                Page count
                Figures: 6, Tables: 0, References: 42, Pages: 4, Words: 0
                Categories
                Subject: Communication
                Subject: Communications
                Subject: G‐Quadruplexes
                Custom metadata
                source-schema-version-number 2.0
                component-id anie201607965
                cover-date December 12, 2016
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.5 mode:remove_FC converted:09.02.2017

                ScienceOpen disciplines: Chemistry
                Keywords: bioinorganic chemistry,dna damage,metalation,photochemistry,ruthenium
                Data availability:
                ScienceOpen disciplines: Chemistry
                Keywords: bioinorganic chemistry, dna damage, metalation, photochemistry, ruthenium

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