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Insight into the toxic effects of cis-dichloridoplatinum(II) complexes containing 7-azaindole halogeno derivatives in tumor cells

Abstract

The cisplatin analogues cis-[PtCl2(3ClHaza)2] (1) and cis-[PtCl2(3IHaza)2] (2) (3ClHaza and 3IHaza are 3-chloro-7-azaindole and 3-iodo-7-azaindole, respectively) are quite toxic to ovarian tumor cells, with moderately better IC50 values than for cisplatin in the cisplatin-sensitive cell line A2780. We investigated potential factors which might be involved in the mechanism underlying the cytotoxic effects of 1 and 2 and compared these factors with those involved in the mechanism underlying the effects of conventional cisplatin. Our data indicate that the higher cytotoxicity of 1 and 2 originates mainly from their efficient cellular accumulation, different effects at the level of cell cycle regulation, and reduced propensity for DNA adduct repair. Studies of their reactivity toward cellular components reveal efficient binding to DNA, which is typically required for an active platinum drug. Further results suggest that 1 and 2 are capable of circumventing resistance to cisplatin induced by alterations in cellular accumulation and DNA repair. Hence, the latter two factors appear to be responsible for differences in the toxicity of 1 or 2, and cisplatin in tumor cells. The results of this work reinforce the idea that direct analogues of conventional cisplatin-containing halogeno-substituted 7-azaindoles offer much promise for the design of novel therapeutic agents.

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Abbreviations

3ClHaza:

3-Chloro-7-azaindole

3IHaza:

3-Iodo-7-azaindole

CT:

Calf thymus

DMF:

N,N′-Dimethylformamide

EtBr:

Ethidium bromide

FAAS:

Flameless atomic absorption spectrometry

GSH:

Glutathione

IC50 :

Compound concentration that produces 50 % cell growth inhibition

ICP-MS:

Inductively coupled plasma mass spectroscopy

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

SD:

Standard deviation

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Acknowledgments

This research was supported by the Czech Science Foundation (grant P301/10/0598) and the Ministry of Education of the Czech Republic (grant LH13096). The research of T.M., and J.P. was also supported by the student project of Palacky University in Olomouc (grant PrF 2013 017). J.K.’s research was also supported by the Operational Program Education for Competitiveness–European Social Fund (CZ 1.07/2.3.00/20.0057) of the Ministry of Education, Youth and Sports of the Czech Republic. P.S. and Z.T. acknowledge funding from the Operational Program Research and Development for Innovations–European Regional Development Fund (CZ.1.05/2.1.00/03.0058) and the Operational Program Education for Competitiveness–European Social Fund (CZ.1.07/2.3.00/20.0017) of the Ministry of Education, Youth and Sports of the Czech Republic.

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Correspondence to Viktor Brabec.

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Muchova, T., Pracharova, J., Starha, P. et al. Insight into the toxic effects of cis-dichloridoplatinum(II) complexes containing 7-azaindole halogeno derivatives in tumor cells. J Biol Inorg Chem 18, 579–589 (2013). https://doi.org/10.1007/s00775-013-1003-7

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  • DOI: https://doi.org/10.1007/s00775-013-1003-7

Keywords

  • Platinum drugs
  • Cytotoxicity
  • Cellular uptake
  • Cell cycle
  • DNA damage
  • DNA repair