Cytotoxicity of a Ti(IV) compound is independent of serum proteins

Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):5016-21. doi: 10.1073/pnas.1119303109. Epub 2012 Mar 12.

Abstract

Titanium(IV) compounds are excellent anticancer drug candidates, but they have yet to find success in clinical applications. A major limitation in developing further compounds has been a general lack of understanding of the mechanism governing their bioactivity. To determine factors necessary for bioactivity, we tested the cytotoxicity of different ligand compounds in conjunction with speciation studies and mass spectrometry bioavailability measurements. These studies demonstrated that the Ti(IV) compound of N,N'-di(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) is cytotoxic to A549 lung cancer cells, unlike those of citrate and naphthalene-2,3-diolate. Although serum proteins are implicated in the activity of Ti(IV) compounds, we found that these interactions do not play a role in [TiO(HBED)](-) activity. Subsequent compound characterization revealed ligand properties necessary for activity. These findings establish the importance of the ligand in the bioactivity of Ti(IV) compounds, provides insights for developing next-generation Ti(IV) anticancer compounds, and reveal [TiO(HBED)](-) as a unique candidate anticancer compound.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Proteins / metabolism*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Chelating Agents / chemistry
  • Chelating Agents / toxicity
  • Chromatography, Liquid
  • Crystallography, X-Ray
  • Dimethylformamide
  • Drug Screening Assays, Antitumor
  • Edetic Acid / analogs & derivatives
  • Edetic Acid / chemistry
  • Edetic Acid / toxicity
  • Humans
  • Hydrogen-Ion Concentration / drug effects
  • Mass Spectrometry
  • Potentiometry
  • Serum Albumin / metabolism
  • Spectrophotometry
  • Titanium / chemistry
  • Titanium / toxicity*
  • Transferrin / metabolism

Substances

  • Blood Proteins
  • Chelating Agents
  • Serum Albumin
  • Transferrin
  • N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid
  • Dimethylformamide
  • Edetic Acid
  • Titanium