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J. Biol. Chem., Vol. 282, Issue 16, 12010-12021, April 20, 2007

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Pro-apoptotic Activity of Novel Isatin-Schiff Base Copper(II) Complexes Depends on Oxidative Stress Induction and Organelle-selective Damage^*

Giuseppe Filomeni¹, Giselle Cerchiaro², Ana Maria Da Costa Ferreira, Angelo De Martino, Jens Z. Pedersen, Giuseppe Rotilio, and Maria R. Ciriolo³

From the Department of Biology, University of Rome "Tor Vergata," Via della Ricerca Scientifica, 00133 Rome, Italy and the Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, P. O. Box 26077, CEP 05513-970 São Paulo, São Paulo, Brazil

We characterized the pro-apoptotic activity of two new synthesized isatin-Schiff base copper(II) complexes, obtained from isatin and 1,3-diaminopropane or 2-(2-aminoethyl)pyridine: (Cu(isapn)) and (Cu(isaepy)₂), respectively. We demonstrated that these compounds trigger apoptosis via the mitochondrial pathway. The early induction of the p53/p21 system indicates a role for p53 in cell death, however, experiments carried out with small interfering RNA against p53, or with cells lacking p53, support that a p53-independent mechanism can also occur. The extent of apoptosis mirrors the kinetics of intracellular copper uptake. Particularly, Cu(isaepy)₂ enters the cells more efficiently and specifically damages nuclei and mitochondria, as evidenced by atomic absorption analysis of copper content and by the extent of nuclear and mitochondrial integrity. Conversely, Cu(isapn), although less permeable, induces a wide-spread oxidative stress, as demonstrated by analyses of reactive oxygen species concentration, and oxidation of proteins and lipids. The increase of the antioxidant defense, through the overexpression of Cu,Zn-SOD, partially counteracts cell death; whereas retinoic acid-mediated differentiation completely rescues cells from apoptosis induced by both compounds. The activation of JNK- and Akt-mediated phosphorylative pathways has been found to be not functional for apoptosis induction. On the contrary, apoptosis significantly decreased when the analogous zinc complex was used or when Cu(isaepy)₂ was incubated in the presence of a copper chelator. Altogether, our data provide evidence for a dual role of these copper(II) complexes: they are able to vehicle copper into the cell, thus producing reactive oxygen species, and could behave as delocalized lipophilic cation-like molecules, thus specifically targeting organelles.

Received for publication, November 27, 2006 , and in revised form, February 22, 2007.

^* This work was supported in part by grants from Ministero della Salute, Ministero dell'Università e della Ricerca (to M. R. C.), Fondo per gli Investimenti della Ricerca di Base (FIRB) (to G. R.), and Brazilian agency Fundação de Amparo à Pesquisa do Estado de São Paulo (to A. M. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S2.

¹ Recipient of fellowship "Santina Grillini" from Italian Association for Cancer Research (AIRC-FIRC).

² Recipient of a fellowship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) while at the University of Rome "Tor Vergata."

³ To whom correspondence should be addressed. Tel.: 39-06-7259-4369; Fax: 39-06-7259-4311; E-mail: ciriolo{at}bio.uniroma2.it.

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