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

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Abstract

An investigation of the molecular mechanism of the anticancer activity demonstrated by the ruthenium(II)–arene compound [Ru(η6-p-cymene)Cl2(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 G2/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 NH2-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 G2/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.

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Acknowledgments

The authors are indebted to the Department of Science and Technology, India, and the Indo Swiss Bilateral Research Initiative (EPFL) for funding this research. The support of the the Austrian Science Fund (C.G.H.; Schrödinger Fellowship J2613-N19) and of COST D39 is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Environmental Science, University of Kalyani, Kalyani, India

    Soumya Chatterjee, Subhadip Kundu & Arindam Bhattacharyya

  2. Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland

    Christian G. Hartinger & Paul J. Dyson

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  1. Soumya Chatterjee
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  2. Subhadip Kundu
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  3. Arindam Bhattacharyya
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  4. Christian G. Hartinger
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  5. Paul J. Dyson
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Correspondence to Arindam Bhattacharyya.

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Chatterjee, S., Kundu, S., Bhattacharyya, A. et al. The ruthenium(II)–arene compound RAPTA-C induces apoptosis in EAC cells through mitochondrial and p53–JNK pathways. J Biol Inorg Chem 13, 1149–1155 (2008). https://doi.org/10.1007/s00775-008-0400-9

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  • DOI: https://doi.org/10.1007/s00775-008-0400-9

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