Cultivated animal cells (mouse peritoneal macrophages, chick fibroblasts or mouse Ehrlich tumor cells) or Zea mays root tips are treated with cis-Pt (II). Various effects (chromatin dispersion or condensation, pycnosis) are observed under some experimental conditions in all cell types. Cytoplasmic ribosomes in helical aggregates appear but only in vegetal cells. Mitosis and cell cycle disturbances due to cis-Pt (II) are probably related to chromatin alterations. We suggest that the latter and helical polyribosomes are produced by cis-Pt (II) reaction with nucleic acids in these structures.
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Sci Rep
January 2020
Department of Biophysics and Cell Biology, University of Debrecen, Faculty of Medicine, Debrecen, H-4032, Hungary.
Unexpectedly, the widely used anticancer agents Cisplatin (Cis-Pt) and Daunorubicin (Dauno) exhibited cell type- and concentration-dependent synergy or antagonism in vitro. We attempted to interpret these effects in terms of the changes elicited by the drugs in the chromatin, the target held primarily responsible for the cytotoxicity of both agents. We measured the effect of Cis-Pt on the levels of Dauno in different cell compartments, the effect of Cis-Pt on Dauno-induced nucleosome eviction, and assessed the influence of Dauno on DNA platination in flow- and laser scanning cytometry as well as in laser ablation-inductively coupled plasma-mass spectrometry assays.
View Article and Find Full Text PDFChem Biol
December 2010
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
The effects of cisplatin binding to DNA were explored at the nucleosome level to incorporate key features of the eukaryotic nuclear environment. An X-ray crystal structure of a site-specifically platinated nucleosome carrying a 1,3-cis-{Pt(NH₃)₂}²+-d(GpTpG) intrastrand cross-link reveals the details of how this adduct dictates the rotational positioning of DNA in the nucleosome. Results from in vitro nucleosome mobility assays indicate that a single platinum adduct interferes with ATP-independent sliding of DNA around the octamer core.
View Article and Find Full Text PDFJ Am Chem Soc
March 2008
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
The mechanism of action of platinum-based anticancer drugs such as cis-diamminedichloroplatinum(II), or cisplatin, involves three early steps: cell entry, drug activation, and target binding. A major target in the cell, responsible for the anticancer activity, is nuclear DNA, which is packaged in nucleosomes that comprise chromatin. It is important to understand the nature of platinum-DNA interactions at the level of the nucleosome.
View Article and Find Full Text PDFJ Am Chem Soc
May 2007
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Cisplatin and carboplatin are used successfully to treat various types of cancer. The drugs target the nucleosomes of cancer cells and form intrastrand DNA cross-links that are located in the major groove. We constructed two site-specifically modified nucleosomes containing defined intrastrand cis-{Pt(NH3)2}(2+) 1,3-d(GpTpG) cross-links.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
August 2005
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
We constructed two site-specifically modified nucleosomes containing an intrastrand cis-{Pt(NH3)2}2+ 1,3-d(GpTpG) cross-link, similar to one formed by the anticancer drugs carboplatin and cisplatin on DNA, and investigated their structures by hydroxyl radical footprinting and exonuclease III digestion. Hydroxyl radical footprinting demonstrated that the presence of the platinum cross-link selects out a specific rotational setting of DNA on the histone octamer core in each of two reconstituted nucleosomes in which the platinum positions differ by half a DNA helical turn. The {Pt(NH3)2}2+ cross-link is situated in a structurally similar location, with the undamaged strand projecting outward, forcing the DNA to adopt opposite rotational settings in its wrapping around the histone octamer in the two nucleosomes.
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