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Binding of topotecan to chromatin: Insights into cooperative binding and comparison with DNA

Masoome Babaei1, Azra Rabbani-Chadegani1, Parinaz Ghadam2

  • 1Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.

International Journal of Biological Macromolecules
|June 21, 2015
PubMed

Insights

Topotecan (TPT), an anticancer drug, binds more strongly to chromatin than DNA. This interaction involves both DNA and histone proteins, influencing TPT's anticancer activity within the cell nucleus.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Topotecan (TPT) is a crucial anticancer agent.
  • Limited research exists on TPT's interaction with DNA-histone complexes in chromatin.

Purpose of the Study:

  • To investigate the binding affinity of Topotecan (TPT) to the DNA-histone complex within chromatin.
  • To elucidate the role of chromatin structure in TPT's anticancer mechanism.

Main Methods:

  • Utilized spectroscopy (UV-Vis, fluorescence, circular dichroism) and equilibrium dialysis.
  • Analyzed TPT's effects on chromatin chromophores and histone protein structure.
  • Quantified binding affinity using association constants.

Main Results:

  • TPT binding decreased fluorescence intensity of histone aromatic residues and UV absorbance.
  • Circular dichroism indicated a reduction in histone alpha-helix content upon TPT binding.
  • TPT exhibited higher binding affinity to chromatin (Ka = 2.65×10^2 M⁻¹) than to DNA alone (Ka = 1.11×10^2 M⁻¹).

Conclusions:

  • Topotecan interacts with both DNA and histone proteins in chromatin.
  • Histone proteins play a significant role in Topotecan's biological action.
  • TPT exerts its anticancer effects by binding to the overall chromatin structure.
Keywords:
ChromatinGenotoxicityHistonesSpectroscopyTopotecan

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