Monoterpenes as drug shuttles: cytotoxic (6-aminomethylnicotinate)dichloridoplatinum(II) complexes with potential to overcome cisplatin resistance

J Med Chem. 2007 Mar 22;50(6):1288-93. doi: 10.1021/jm061379o. Epub 2007 Mar 1.

Abstract

(6-Aminomethylnicotinate)dichloridoplatinum(II) complexes 4 esterified with terpene alcohols were tested on a panel of five human tumor cell lines. While they were accumulated in all cell lines more readily than cisplatin (CDDP), their cytotoxicities were tumor-specific and structure-dependent. Cell lines known to feature elevated levels of antiapoptotic, ion-channel-affecting proteins or otherwise impaired caspase-9 activation responded better to 4 than to CDDP, e.g., the HL-60 leukemia to the fenchyl and bornyl derivatives 4a,b at an IC90 < or = 10 microM. The (-)-menthyl complex 4g was far better accumulated and more efficacious in CDDP-resistant 1411HP male germ cell tumor cells than in the congenerous CDDP-sensitive H12.1 cell line. 4g also broke the CDDP resistance of 518A2 melanoma cells. Cell decay in each case was apoptotic as to TUNEL and Annexin V fluorescence assays. Some complexes 4 seem to positively modulate the permeability of the cell membrane and of blocked mitochondrial anion channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Cisplatin / pharmacology*
  • DNA / chemistry
  • Drug Resistance, Neoplasm*
  • Drug Screening Assays, Antitumor
  • Electrophoresis, Gel, Two-Dimensional
  • Humans
  • In Situ Nick-End Labeling
  • Male
  • Monoterpenes / chemistry*
  • Necrosis
  • Organoplatinum Compounds / chemical synthesis
  • Organoplatinum Compounds / chemistry
  • Organoplatinum Compounds / pharmacology*
  • Plasmids
  • Spectrophotometry, Atomic

Substances

  • Antineoplastic Agents
  • Monoterpenes
  • Organoplatinum Compounds
  • DNA
  • Cisplatin