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DNA and glutathione interactions in cell-free media of asymmetric platinum(II) complexes cis- and trans-[PtCl2(isopropylamine)(1-methylimidazole)]: relations to their different antitumor effects

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Abstract

The global modification of mammalian and plasmid DNAs by the novel platinum compounds cis-[PtCl2(isopropylamine)(1-methylimidazole)] and trans-[PtCl2(isopropylamine)(1-methylimidazole)] and the reactivity of these compounds with reduced glutathione (GSH) were investigated in cell-free media using various biochemical and biophysical methods. Earlier cytotoxicity studies had revealed that the replacement of the NH3 groups in cisplatin by the azole and isopropylamine ligands lowers the activity of cisplatin in both sensitive and resistant cell lines. The results of the present work show that this replacement does not considerably affect the DNA modifications by this drug, recognition of these modifications by HMGB1 protein, their repair, and reactivity of the platinum complex with GSH. These results were interpreted to mean that the reduced activity of this analog of cisplatin in tumor cell lines is due to factors that do not operate at the level of the target DNA. In contrast, earlier studies had shown that the replacement of the NH3 groups in the clinically ineffective trans isomer (transplatin) by the azole and isopropylamine ligands results in a radical enhancement of its activity in tumor cell lines. Importantly, this replacement also markedly alters the DNA binding mode of transplatin, which is distinctly different from that of cisplatin, but does not affect reactivity with GSH. Hence, the results of the present work are consistent with the view and support the hypothesis systematically tested by us and others that platinum drugs that bind to DNA in a fundamentally different manner from that of conventional cisplatin may have altered pharmacological properties.

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Abbreviations

bp:

Base pair

CD:

Circular dichroism

CFE:

Cell-free extract

CL:

Cross-link

CT:

Calf thymus

DPP:

Differential pulse polarography

EtBr:

Ethidium bromide

FAAS:

Flameless atomic absorption spectrophotometry

GSH:

Glutathione

KF:

Klenow fragment from DNA polymerase I (exonuclease minus, mutated to remove the 3′ → 5′ proofreading domain)

Tris:

Tris(hydroxymethyl)aminomethane

TU:

Thiourea

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Acknowledgments

This research was supported by the Ministry of Education of the Czech Republic (MSMT LC06030, 6198959216, ME08017, OC08003), the Academy of Sciences of the Czech Republic (grants 1QS500040581, KAN200200651, AV0Z50040507 and AV0Z50040702), the Grant Agency of the Academy or Sciences of the Czech Republic (IAA400040803), and the Grant Agency of the Ministry of Health of the Czech Republic (NR8562-4/2005). J.K. is an international research scholar of the Howard Hughes Medical Institute. The synthesis of the compounds by Elena Pantoja is kindly acknowledged. The authors also acknowledge that their participation in the EU COST Action D39 enabled them to exchange regularly the most recent ideas in the field of anticancer metallodrugs with several European colleagues.

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Authors and Affiliations

  1. Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 61265, Brno, Czech Republic

    Tereza Suchánková, Marie Vojtíšková, Viktor Brabec & Jana Kašpárková

  2. Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands

    Jan Reedijk

  3. Laboratory of Biophysics, Department of Experimental Physics, Faculty of Sciences, Palacky University, tr. Svobody 26, 77146, Olomouc, Czech Republic

    Viktor Brabec

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  1. Tereza Suchánková
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  2. Marie Vojtíšková
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  3. Jan Reedijk
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  4. Viktor Brabec
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  5. Jana Kašpárková
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Correspondence to Jana Kašpárková.

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Suchánková, T., Vojtíšková, M., Reedijk, J. et al. DNA and glutathione interactions in cell-free media of asymmetric platinum(II) complexes cis- and trans-[PtCl2(isopropylamine)(1-methylimidazole)]: relations to their different antitumor effects. J Biol Inorg Chem 14, 75–87 (2009). https://doi.org/10.1007/s00775-008-0425-0

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