Mechanisms underlying the cytotoxic effects of Tachpyr--a novel metal chelator.

Academic Article


  • Tachpyr (N,N'N"-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane), a novel metal chelator, was previously shown to deplete intracellular iron and exert a cytotoxic effect on cultured bladder cancer cells. Tachpyr binds Fe(II) and readily reduces Fe(III). The iron(II)-Tachpyr chelate undergoes intramolecular oxidative dehydrogenation resulting in mono- and diimino Fe(II) complexes. The present study investigates the redox-activity of the Tachpyr-iron complex to better define the mechanism of Tachpyr's cytotoxicity. Tachpyr's mechanism of cytotoxicity was studied using cell-free solutions, isolated DNA, and cultured mammalian cells by employing UV-VIS spectrophotometry, oximetry, spin-trapping technique, and electron paramagnetic resonance (EPR) spectrometry. The results show that: (1) Tachpyr by itself after 24 h of incubation had a cytotoxic effect on cultured cells; (2) fully oxidized Tachpyr had no cytotoxic effects on cultured cells even after 24 h of incubation; (3) Tachpyr protected isolated DNA against H(2)O(2)-induced damage, but not against HX/XO-induced damage; and (4) Tachpyr-Fe(II) chelate slows down but does not block oxidation of Fe(II), allows O*(-)(2)-induced or Tachpyr-induced reduction of Fe(III), and consequently promotes production of *OH through the Haber-Weiss reaction cycle. The results indicate that Tachpyr can protect cells against short-term, metal-mediated damage. However, upon prolonged incubation, Tachpyr exerts cytotoxic effects. Therefore, in addition to iron depletion, low-level oxidative stress, which in part occurs because of redox cycling of the coordinated iron ion, may contribute to the cytotoxic effects of Tachpyr.
  • Authors

  • Samuni, Ayelet M
  • Krishna, Murali C
  • DeGraff, William
  • Russo, Angelo
  • Planalp, Roy
  • Brechbiel, Martin W
  • Mitchell, James B
  • Status

    Publication Date

  • July 3, 2002
  • Published In


  • Antineoplastic Agents
  • Carcinoma
  • Catalase
  • Cell Survival
  • Cell-Free System
  • Chelating Agents
  • Cyclohexylamines
  • DNA
  • DNA, Single-Stranded
  • Dose-Response Relationship, Drug
  • Humans
  • Iron
  • Lung Neoplasms
  • Macromolecular Substances
  • Oxidation-Reduction
  • Oxygen
  • Oxygen Consumption
  • Plasmids
  • Pyridines
  • Superoxide Dismutase
  • Tumor Cells, Cultured
  • Tumor Stem Cell Assay
  • Digital Object Identifier (doi)

    Pubmed Id

  • 12090935
  • Start Page

  • 211
  • End Page

  • 218
  • Volume

  • 1571
  • Issue

  • 3