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Enhancing lipophilicity as a strategy to overcome resistance against platinum complexes?

Irina Buss1, Dirk Garmann, Mathea S Galanski

  • 1Institute of Pharmacy, University of Bonn, Bonn, Germany. i.buss@uni-bonn.de

Journal of Inorganic Biochemistry
|April 1, 2011
PubMed

Insights

Enhancing the lipophilicity of platinum complexes did not overcome drug resistance. While more lipophilic platinum analogues showed increased early influx, they also exhibited reduced cytotoxicity and did not effectively combat resistance in all tested cancer cell lines.

Area of Science:

  • Pharmacology and Toxicology
  • Cancer Biology
  • Medicinal Chemistry

Background:

  • Decreased cellular influx is a key mechanism of platinum-based chemotherapy resistance.
  • Strategies to overcome platinum resistance, such as modifying drug lipophilicity, require thorough investigation.

Purpose of the Study:

  • To determine if enhancing lipophilicity of platinum complexes can overcome decreased influx-mediated resistance.
  • To investigate the impact of lipophilicity on cellular accumulation, DNA platination, and cytotoxicity of oxaliplatin analogues.

Main Methods:

  • Synthesis and evaluation of oxaliplatin analogues with varying lipophilicity.
  • Measurement of cellular accumulation, DNA platination, and cytotoxicity in cisplatin- and oxaliplatin-resistant cell lines (A2780/A2780cis, HCT-8/HCT-8ox).
  • Quantification of platinum concentrations using flameless atomic absorption spectrometry and adsorptive stripping voltammetry.

Main Results:

  • Passive diffusion was the primary influx mechanism for lipophilic oxaliplatin analogues in early incubation.
  • Increased lipophilicity correlated with higher early influx but reduced overall cytotoxic activity.
  • Differential effects on resistance were observed: HCT-8ox cells showed reduced resistance to more lipophilic compounds, while A2780cis cells maintained resistance.
  • Reduced resistance in HCT-8ox cells was not solely due to increased influx, suggesting circumvention of other resistance mechanisms.

Conclusions:

  • Enhancing lipophilicity of platinum complexes is not a successful strategy to overcome platinum resistance.
  • Higher lipophilicity is associated with decreased cytotoxic activity, counteracting potential benefits from altered influx.
  • The complex interplay between lipophilicity, influx, and cellular resistance mechanisms warrants further research.

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