Protein phosphatase 2A inhibition and circumvention of cisplatin cross-resistance by novel TCM-platinum anticancer agents containing demethylcantharidin

Bioorg Med Chem. 2004 Sep 1;12(17):4565-73. doi: 10.1016/j.bmc.2004.07.009.

Abstract

Novel TCM-platinum compounds [Pt(C(8)H(8)O(5))(NH(2)R)(2)] 1-5, derived from integrating demethylcantharidin, a modified component from a traditional Chinese medicine (TCM) with a platinum moiety, possess anticancer and protein phosphatase 2A inhibition properties. The compounds are able to circumvent cisplatin resistance by apparently targeting the DNA repair mechanism. Novel isosteric analogues [Pt(C(9)H(10)O(4))(NH(2)R)(2)] A and B, devoid of PP2A-inhibitory activity, were found to suffer from an enhanced DNA repair and were cross-resistant to cisplatin. The results advocate a well-defined structure-activity requirement associating the PP2A-inhibiting demethylcantharidin with the circumvention of cisplatin cross-resistance demonstrated by TCM-Pt compounds 1-5.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / chemical synthesis*
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Cantharidin / analogs & derivatives*
  • Cantharidin / pharmacology
  • Cisplatin / analogs & derivatives*
  • Cisplatin / pharmacology
  • Cross-Linking Reagents / chemical synthesis
  • DNA Repair / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Male
  • Medicine, Chinese Traditional
  • Organoplatinum Compounds / chemical synthesis*
  • Organoplatinum Compounds / pharmacology
  • Phosphoprotein Phosphatases / antagonists & inhibitors*
  • Protein Phosphatase 2
  • Structure-Activity Relationship
  • Time Factors
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents, Phytogenic
  • Cross-Linking Reagents
  • Enzyme Inhibitors
  • Organoplatinum Compounds
  • demethylcantharidin
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2
  • Cantharidin
  • Cisplatin