CpG methylation increases the DNA binding of 9-aminoacridine carboxamide Pt analogues |
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| Institution: | 1. Cátedra de Inmunología, Departamento de Biociencias, Facultad de Química, Universidad de la República, Avda Alfredo Navarro 3051, piso 2, CP 11600 Montevideo, Uruguay;2. Instituto de Microbiología y Parasitología Médica, Facultad de Medicina, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Tecnológicas (IMPaM, UBA-CONICET), Paraguay 2155, piso 13, C1121ABG Buenos Aires, Argentina;1. Faculty of Chemistry, University of Wroclaw, Joliot-Curie 14, 50-383 Wroclaw, Poland;2. Universidade do Minho, Centro de Fisica, Campus de Gualtar, 4710-057 Braga, Portugal;3. Universidade d Minho, Centro de Fisica, Campus de Gualtar, 4710-057 Braga, Portugal;4. Department of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznań, Poland;1. The Institute of Chemistry and the Center for Nanoscience, The Hebrew University of Jerusalem, Israel;2. The Faculty of Chemistry, The Weizmann Institute of Science, Israel;1. Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan;2. Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan |
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| Abstract: | This study investigated the effect of CpG methylation on the DNA binding of cisplatin analogues with an attached aminoacridine intercalator. DNA-targeted 9-aminoacridine carboxamide Pt complexes are known to bind at 5′-CpG sequences. Their binding to methylated and non-methylated 5′-CpG sequences was determined and compared with cisplatin. The damage profiles of each platinum compound were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. Methylation at 5′-CpG was shown to significantly increase the binding intensity for the 9-aminoacridine carboxamide compounds, whereas no significant increase was found for cisplatin. 5′-CpG methylation had the largest effect on the 9-ethanolamine-acridine carboxamide Pt complex, followed by the 9-aminoacridine carboxamide Pt complex and the 7-fluoro complex. The methylation state of a cell’s genome is important in maintaining normal gene expression, and is often aberrantly altered in cancer cells. An analogue of cisplatin which differentially targets methylated DNA may be able to improve its therapeutic activity, or alter its range of targets and evade the chemoresistance which hampers cisplatin efficacy in clinical use. |
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| Keywords: | 9-Aminoacridine Anticancer drug Cisplatin Cisplatin analogues DNA sequence specificity Methylation Polymerase stop assay |
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