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

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.
AuthorsSoumya Chatterjee, Subhadip Kundu, Arindam Bhattacharyya, Christian G Hartinger, Paul J Dyson
JournalJournal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry (J Biol Inorg Chem) Vol. 13 Issue 7 Pg. 1149-55 (Sep 2008) ISSN: 1432-1327 [Electronic] Germany
PMID18597125 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 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
Topics
  • 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, 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, metabolism)
  • Organometallic Compounds (pharmacology)
  • Signal Transduction (drug effects)
  • Tumor Suppressor Protein p53 (metabolism)
  • bcl-2-Associated X Protein (metabolism)

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