Cytotoxic evaluation of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in peripheral blood lymphocytes of patients with refractory solid tumors using electron paramagnetic resonance

Jill M. Kolesar, Kamakshi Sachidanandam, William R. Schelman, Jens Eickhoff, Kyle D. Holen, Anne M. Traynor, Dona B. Alberti, James P. Thomas, Christopher R. Chitambar, George Wilding, William E. Antholine

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-APAP) is a metal chelator that potently inhibits the enzyme ribonucleotide reductase (RRRR), which plays a key role in cell division and tumor progression. A subunit of RRRR has a non-heme iron and a tyrosine-free radical, which are required for the enzymatic reduction of ribonucleotides to deoxyribonucleotides. The objective of the present study was to determine whether 3-APAP affects its targeted action by measuring electron paramagnetic resonance (EPRPR) signals formed either directly or indirectly from low molecular weight ferric-3-APAP chelates. Peripheral blood lymphocytes were collected from patients with refractory solid tumors at baseline and at 2, 4.5 and 22h after 3-APAP administration. Using EPRPR spectra, our study identified signals from high-spin Fe-transferrin, high-spin heme and low-spin iron or copper ions. An increase in the Fe-transferrin signal was observed, suggesting blockage of Fe uptake. It is hypothesized that formation of reactive oxygen species by FeT2 or CuT damages the transferrin or the transferrin receptor. An increase in the heme signal was also observed, which was a probable source of cytochromec release from the mitochondria and potential apoptosis. In addition, increased levels of Fe and Cu were identified. These results, which were consistent with our previous study validating 3-AP-mediated signals by EPR, provide valuable insights into the in vivo mechanism of action of 3-AP.

Original languageEnglish
Pages (from-to)119-123
Number of pages5
JournalExperimental and Therapeutic Medicine
Volume2
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
  • Chelator
  • Electron paramagnetic resonance
  • Ribonucleotide reductase

ASJC Scopus subject areas

  • Immunology and Microbiology (miscellaneous)
  • Cancer Research

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