The ruthenium(II)-arene compound RAPTA-C induces apoptosis in EAC cells through mitochondrial and p53-JNK pathways

J Biol Inorg Chem. 2008 Sep;13(7):1149-55. doi: 10.1007/s00775-008-0400-9. Epub 2008 Jul 3.

Abstract

An investigation of the molecular mechanism of the anticancer activity demonstrated by the ruthenium(II)-arene compound [Ru(eta(6)-p-cymene)Cl(2)(pta)] (pta is 1,3,5-triaza-7-phosphaadamantane), termed "RAPTA-C", in Ehrlich ascites carcinoma (EAC) bearing mice is described. RAPTA-C exhibits effective cell growth inhibition by triggering G(2)/M phase arrest and apoptosis in cancer cells. Cell cycle arrest is associated with increased levels of p21 and reduced amounts of cyclin E. RAPTA-C treatment also enhances the levels of p53, and its treatment triggers the mitochondrial apoptotic pathway, as shown by the change in Bax to Bcl-2 ratios, resulting in cytochrome c release and caspase-9 activation. c-Jun NH(2)-terminal kinase (JNK) is a critical mediator in RAPTA-C-induced cell growth inhibition. Activation of JNK by RAPTA-C increases significantly during apoptosis. Overall, these results suggest a critical role for JNK and p53 in RAPTA-C-induced G(2)/M arrest and apoptosis of EAC-bearing mice. Consequently, RAPTA-C treatment results in a significant inhibition in the progression of cancer in an animal model, which emulates the human disease, and does so with remarkably low general toxicity; hence, RAPTA-C has potential for clinical application.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Carcinoma, Ehrlich Tumor / pathology*
  • Caspase 9 / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Cymenes
  • Cytochromes c / metabolism
  • DNA / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Organometallic Compounds / pharmacology*
  • Signal Transduction / drug effects*
  • Tumor Suppressor Protein p53 / metabolism*
  • bcl-2-Associated X Protein / metabolism

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Cymenes
  • Organometallic Compounds
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • dichloro(4-cymene)(1,3,5-triaza-7-phosphatricyclo(3.3.1.1)decane)ruthenium(II)
  • Cytochromes c
  • DNA
  • JNK Mitogen-Activated Protein Kinases
  • Caspase 9