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

  • Tereza Muchova
  • Jitka Pracharova
  • Pavel Starha
  • Radana Olivova
  • Oldrich Vrana
  • Barbora Benesova
  • Jana Kasparkova
  • Zdenek Travnicek
  • Viktor Brabec
Original Paper

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.

Graphical abstract

Keywords

Platinum drugs Cytotoxicity Cellular uptake Cell cycle DNA damage DNA repair 

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

Supplementary material

775_2013_1003_MOESM1_ESM.pdf (240 kb)
Supplementary material 1 (PDF 239 kb)

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Copyright information

© SBIC 2013

Authors and Affiliations

  • Tereza Muchova
    • 1
  • Jitka Pracharova
    • 1
  • Pavel Starha
    • 2
  • Radana Olivova
    • 1
  • Oldrich Vrana
    • 3
  • Barbora Benesova
    • 1
  • Jana Kasparkova
    • 1
  • Zdenek Travnicek
    • 2
  • Viktor Brabec
    • 3
  1. 1.Department of Biophysics, Faculty of SciencesPalacky UniversityOlomoucCzech Republic
  2. 2.Department of Inorganic Chemistry, Faculty of Science, Regional Centre of Advanced Technologies and MaterialsPalacky UniversityOlomoucCzech Republic
  3. 3.Institute of BiophysicsAcademy of Sciences of the Czech RepublicBrnoCzech Republic

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