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Breast anticancer drug tamoxifen and its metabolites bind tRNA at multiple sites

P Bourassa1, T J Thomas2, J Bariyanga3

  • 1Department of Chemistry-Physics, University of Québec in Trois-Rivières, C. P. 500, Trois-Rivières, Québec G9A 5H7, Canada.

International Journal of Biological Macromolecules
|September 30, 2014
PubMed

Insights

Breast cancer drug tamoxifen and its metabolites bind to transfer RNA (tRNA) at multiple sites. 4-hydroxy-tamoxifen exhibits the strongest binding affinity, influencing tRNA structure minimally at low concentrations.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Tamoxifen is a widely used drug for treating estrogen receptor-positive breast cancer.
  • Understanding drug-target interactions at a molecular level is crucial for drug development and efficacy.
  • Transfer RNA (tRNA) plays essential roles in protein synthesis and can be a target for small molecules.

Purpose of the Study:

  • To investigate the binding interactions between tamoxifen and its major metabolites (4-hydroxytamoxifen and endoxifen) with tRNA.
  • To determine the binding sites, affinity, and structural consequences of these interactions.
  • To elucidate the molecular mechanisms underlying tamoxifen's action at the tRNA level.

Main Methods:

  • Fourier-transform infrared (FTIR) spectroscopy
  • Circular dichroism (CD) spectroscopy
  • UV-visible spectroscopy
  • Fluorescence spectroscopy
  • Molecular docking simulations

Main Results:

  • Tamoxifen and its metabolites bind to tRNA at multiple sites with significant binding constants.
  • The binding affinity order was determined as 4-hydroxytamoxifen > tamoxifen > endoxifen.
  • Molecular docking revealed interactions with specific nucleobases, with calculated free binding energies.
  • tRNA conformation remained largely unchanged (A-family structure), but biopolymer aggregation was observed at high drug concentrations.

Conclusions:

  • Tamoxifen and its metabolites interact with tRNA, suggesting a potential alternative mechanism of action.
  • The differential binding affinities of tamoxifen and its metabolites to tRNA may influence their pharmacological profiles.
  • While tRNA structure is preserved, high drug concentrations can induce aggregation, warranting further investigation into cellular effects.
Keywords:
4-hydroxtamox4-hydroxytamoxifenBinding siteCDcircular dichroismFTIRFourier transform infrared spectroscopyModelingSpectroscopyTamoxifenendoxendoxifentRNAtamoxtamoxifen

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