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Effects of cytotoxic cis- and trans-diammine monochlorido platinum(II) complexes on selenium-dependent redox enzymes and DNA
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SYSNO ASEP 0486052 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Effects of cytotoxic cis- and trans-diammine monochlorido platinum(II) complexes on selenium-dependent redox enzymes and DNA Author(s) Lemmerhirt, H. (DE)
Behnisch, S. (DE)
Bodtke, A. (DE)
Lillig, Ch.H. (DE)
Pazderová, L. (CZ)
Kašpárková, Jana (BFU-R) RID, ORCID
Brabec, Viktor (BFU-R) RID, ORCID
Bednarski, P.J. (DE)Number of authors 8 Source Title Journal of Inorganic Biochemistry. - : Elsevier - ISSN 0162-0134
Roč. 178, JAN2018 (2018), s. 94-105Number of pages 12 s. Publication form Print - P Language eng - English Country US - United States Keywords glutathione-peroxidase ; thioredoxin reductase Subject RIV CE - Biochemistry OECD category Biochemistry and molecular biology R&D Projects GA17-09436S GA ČR - Czech Science Foundation (CSF) Institutional support BFU-R - RVO:68081707 UT WOS 000419999600010 DOI https://doi.org/10.1016/j.jinorgbio.2017.10.011 Annotation Here we present the preparation of 14 pairs of cis-and trans-diammine monochlorido platinum(II) complexes, coordinated to heterocycles (i.e., imidazole, 2-methylimidazole and pyrazole) and linked to various acylhydrazones, which were designed as potential inhibitors of the selenium-dependent enzymes glutathione peroxidase 1 (GPx-1) and thioredoxin reductase 1 (TrxR-1). However, no inhibition of bovine GPx-1 and only weak inhibition of murine TrxR-1 was observed in in vitro assays. Nonetheless, the cis configured diammine monochlorido Pt(II) complexes exhibited cytotoxic and apoptotic properties on various human cancer cell lines, whereas the trans configured complexes generally showed weaker potency with a few exceptions. On the other hand, the trans complexes were generally more likely to lack cross-resistance to cisplatin than the cis analogues. Platinum was found bound to the nuclear DNA of cancer cells treated with representative Pt complexes, suggesting that DNA might be a possible target. Thus, detailed in vitro binding experiments with DNA were conducted. Interactions of the compounds with calf thymus DNA were investigated, including Pt binding kinetics, circular dichroism (CD) spectral changes, changes in DNA melting temperatures, unwinding of supercoiled plasmids and ethidium bromide displacement in DNA. The CD results indicate that the most active cis configured pyrazole-derived complex causes unique structural changes in the DNA compared to the other complexes as well as to those caused by cisplatin, suggesting a denaturation of the DNA structure. This may be important for the antiproliferative activity of this compound in the cancer cells. Workplace Institute of Biophysics Contact Jana Poláková, polakova@ibp.cz, Tel.: 541 517 244 Year of Publishing 2018
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