Tumor cell cytotoxicity of a novel metal chelator.
We have synthesized a novel six-coordinate metal chelator from the triamine cis-1,3,5-triaminocyclohexane by the addition of a 2-pyridylmethyl pendant arm on each nitrogen, which we term tachpyr. The experiments described here were designed to explore whether this compound exhibits potential antitumor activity. When added to MBT2 or T24 cultured bladder cancer cells, tachpyr was profoundly cytotoxic, with an IC50 of approximately 4.6 micromol/L compared with 70 micromol/L for desferioxamine. To explore the mode of action of tachpyr, several metal complexes were prepared, including Fe(II), Ca(II), Mn(II), Mg(II), Cu(II), and Zn(II) tachpyr complexes. Of these, the Zn(II), Cu(II), and Fe(II) complexes were without toxic effect, whereas the Ca(II), Mn(II), and Mg(II) complexes remained cytotoxic. To further probe the role of Zn(II) and Cu(II) chelation in the cytotoxicity of tachpyr, sterically hindered tachpyr derivatives were prepared through N-alkylation of tachpyr. These derivatives were unable to strongly bind Fe(III) or Fe(II) but were able to bind Zn(II) and Cu(II). When added to cells, these sterically hindered tachpyr derivatives were nontoxic, consistent with a role of iron depletion in the cytotoxic mechanism of tachpyr. Further, the addition of tachpyr to proliferating cultures resulted in an early and selective inhibition of ferritin synthesis, an iron storage protein whose translation is critically dependent on intracellular iron pools. Taken together, these experiments suggest that tachpyr is a cytotoxic metal chelator that targets intracellular iron, and that the use of tachpyr in cancer therapy deserves further exploration.
Department of Biochemistry, Wake Forest University School of Medicine and the Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC 27157-1082, USA.
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Torti
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Whitman
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Brechbiel
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Park
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D000478:Alkylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002413:Cations, Divalent; D002455:Cell Division; D002478:Cells, Cultured; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003514:Cyclohexylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003676:Deferoxamine / Q000494:pharmacology; D005293:Ferritins / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D008968:Molecular Conformation; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000473:pathology
D000970:Antineoplastic Agents; D002413:Cations, Divalent; D002614:Chelating Agents; D003514:Cyclohexylamines; D011725:Pyridines; C114047:tachpyr; D005293:Ferritins; D007501:Iron; D003676:Deferoxamine