Pro-apoptotic activity of novel isatin-Schiff base copper(II) complexes depends on oxidative stress induction and organelle-selective damage

Giuseppe Filomeni, Giselle Cerchiaro, Ana Maria Da Costa Ferreira, Angelo De Martino, Jens Z. Pedersen, Giuseppe Rotilio, Maria R. Ciriolo

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

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 widespread 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.

Original languageEnglish
Pages (from-to)12010-12021
Number of pages12
JournalJournal of Biological Chemistry
Volume282
Issue number16
DOIs
Publication statusPublished - Apr 20 2007

Fingerprint

Isatin
Oxidative stress
Schiff Bases
Organelles
Copper
Oxidative Stress
Apoptosis
Cell death
Reactive Oxygen Species
Cell Death
Mitochondria
Chelating Agents
Tretinoin
Small Interfering RNA
Cations
Zinc
Antioxidants
Chemical activation
Lipids
Oxidation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Pro-apoptotic activity of novel isatin-Schiff base copper(II) complexes depends on oxidative stress induction and organelle-selective damage. / Filomeni, Giuseppe; Cerchiaro, Giselle; Da Costa Ferreira, Ana Maria; De Martino, Angelo; Pedersen, Jens Z.; Rotilio, Giuseppe; Ciriolo, Maria R.

In: Journal of Biological Chemistry, Vol. 282, No. 16, 20.04.2007, p. 12010-12021.

Research output: Contribution to journalArticle

Filomeni, Giuseppe ; Cerchiaro, Giselle ; Da Costa Ferreira, Ana Maria ; De Martino, Angelo ; Pedersen, Jens Z. ; Rotilio, Giuseppe ; Ciriolo, Maria R. / Pro-apoptotic activity of novel isatin-Schiff base copper(II) complexes depends on oxidative stress induction and organelle-selective damage. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 16. pp. 12010-12021.
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AU - Filomeni, Giuseppe

AU - Cerchiaro, Giselle

AU - Da Costa Ferreira, Ana Maria

AU - De Martino, Angelo

AU - Pedersen, Jens Z.

AU - Rotilio, Giuseppe

AU - Ciriolo, Maria R.

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N2 - 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 widespread 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.

AB - 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 widespread 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.

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