This journal is © The Royal Society of Chemistry 2019 Metallomics, 2019, 11, 1729--1742 | 1729 Cite this: Metallomics, 2019, 11, 1729 Cytotoxic activity of copper(II), nickel(II) and platinum(II) thiosemicarbazone derivatives: interaction with DNA and the H2A histone peptide† Franco Bisceglie, abc Nicolo ` Orsoni, a Marianna Pioli, a Beatrice Bonati, a Pieralberto Tarasconi, ac Claudio Rivetti, a Davide Amidani, a Serena Montalbano, a Annamaria Buschini* abc and Giorgio Pelosi * abc Metal complexes still represent promising pharmacological tools in the development of new anticancer drugs. Bis(citronellalthiosemicarbazonate)nickel(II) is a metal compound extremely effective against leukemic and NCS cancer cell lines. Preliminary experiments performed with this compound and with its Cu(II) and Pt(II) analogues evidenced alterations, detectable by comet assay, in the DNA of treated U937 cells. In addition, [Cu(tcitr) 2 ] and [Pt(tcitr) 2 ] were also able to induce gene mutations and produce frameshift events. To gain further insights into the mechanism of action of these metal compounds, we carried out a multidisciplinary study to investigate whether their biological activity can be ascribed to the direct interaction with DNA or with chromatin. The DNA interaction was investigated by means of CD and UV-Vis spectroscopic techniques and by AFM, whereas the chromatin interaction was studied by analyzing the effects of the compounds on the structure of a peptide that mimicks the potential metal binding site in the ‘‘C-tail’’ region of histone H2A by means of NMR, CD, UV-Vis and MS. The intensities of the effects induced by the metal compounds on the peptide follow the order [Ni(tcitr) 2 ] 4 [Pt(tcitr) 2 ] c [Cu(tcitr) 2 ]. From the AFM data, a remarkable DNA compaction was observed in the presence of [Pt(tcitr) 2 ], while [Ni(tcitr) 2 ] causes the formation of large interlaced DNA aggregates. Significance to metallomics We report the behaviour of three complexes containing the same ligand which have different biological effects. The effects observed were typical of interactions with genomic targets, but it was not clear if they were direct interactions with DNA or indirect interactions with histones. We investigated the direct interactions by AFM and spectroscopic techniques, and the indirect interactions by perturbations induced by the metal complexes on a peptide that mimicks the ‘‘C-tail’’ of histone H2A. The ligand and the metal ions do not have effects on DNA and on the histone-tail, while significant effects are observed in the presence of the metal complexes. Introduction In recent years, research of new anticancer therapies has been oriented towards the use of monoclonal antibodies; 1 however, the development of metal complexes that interact with DNA or proteins 2 still represents a promising pharmacological approach for the treatment of cancer. 3 For instance, cis-diamminedichlorido- platinum(II) (cisplatin) and its analogues are still widely and effectively used anticancer drugs, regardless of their elevated levels of toxicity and the emergence of intrinsic or acquired resistance in some cancer types. 4 In a search aimed to overcome these draw- backs, many efforts have been made towards developing new metal based anticancer drugs that do not present such side effects. 5 The anticancer activity of cisplatin derivatives seems to be due mainly to their direct interaction with DNA. 6 It is therefore of interest to investigate coordination compounds containing different metal ions and the same ligands, 7 active against the proliferation of cancerous cells, in order to understand the role of the metal in their biological activity. 8 a Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 11/a, 43124 Parma, Italy. E-mail: giorgio.pelosi@unipr.it b COMT – Centre for Molecular and Translational Oncology, Department of Chemical and Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy c CIRCMSB – Inter-University Consortium for Research on Chemistry of Metals in Biological Systems, Parma Unit, Parco Area delle Scienze 17/A, 43124 Parma, Italy † Electronic supplementary information (ESI) available. CCDC 1894193. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/ c9mt00166b Received 26th June 2019, Accepted 30th August 2019 DOI: 10.1039/c9mt00166b rsc.li/metallomics Metallomics PAPER Downloaded from https://academic.oup.com/metallomics/article/11/10/1729/5959838 by guest on 25 February 2023