The isatin-Schiff base copper(II) complex Cu(isaepy)2 acts as delocalized lipophilic cation, yields widespread mitochondrial oxidative damage and induces AMP-activated protein kinase-dependent apoptosis

Giuseppe Filomeni, Sara Piccirillo, Ilaria Graziani, Simone Cardaci, Ana M. Da Costa Ferreira, Giuseppe Rotilio, Maria R. Ciriolo

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

We previously demonstrated that Bis[(2-oxindol-3-ylimino)-2- (2-aminoethyl)pyridine-N,N′]copper(II) [Cu(isaepy)2] was an efficient inducer of the apoptotic mitochondrial pathway. Here, we deeply dissect the mechanisms underlying the ability of Cu(isaepy)2 to cause mitochondriotoxicity. In particular, we demonstrate that Cu(isaepy)2 increases NADH-dependent oxygen consumption of isolated mitochondria and that this phenomenon is associated with oxy-radical production and insensitive to adenosine diphosphate. These data indicate that Cu(isaepy)2 behaves as an uncoupler and this property is also confirmed in cell systems. Particularly, SH-SY5Y cells show: (i) an early loss of mitochondrial transmembrane potential; (ii) a decrease in the expression levels of respiratory complex components and (iii) a significant adenosine triphosphate (ATP) decrement. The causative energetic impairment mediated by Cu(isaepy)2 in apoptosis is confirmed by experiments carried out with ρ0 cells, or by glucose supplementation, where cell death is significantly inhibited. Moreover, gastric and cervix carcinoma AGS and HeLa cells, which rely most of their ATP production on oxidative phosphorylation, show a marked sensitivity toward Cu(isaepy)2. Adenosine monophosphate-activated protein kinase (AMPK), which is activated by events increasing the adenosine monophosphate:ATP ratio, is deeply involved in the apoptotic process because the overexpression of its dominant/negative form completely abolishes cell death. Upon glucose supplementation, AMPK is not activated, confirming its role as fuel-sensing enzyme that positively responds to Cu(isaepy)2 -mediated energetic impairment by committing cells to apoptosis. Overall, data obtained indicate that Cu(isaepy)2 behaves as delocalized lipophilic cation and induces mitochondrial-sited reactive oxygen species production. This event results in mitochondrial dysfunction and ATP decrease, which in turn triggers AMPK-dependent apoptosis.

Original languageEnglish
Pages (from-to)1115-1124
Number of pages10
JournalCarcinogenesis
Volume30
Issue number7
DOIs
Publication statusPublished - 2009

Fingerprint

Isatin
AMP-Activated Protein Kinases
Schiff Bases
Cations
Copper
Apoptosis
Adenosine Monophosphate
Adenosine Triphosphate
Protein Kinases
Cell Death
Glucose
bis((2-oxindol-3-ylimino)-2-(2-aminoethyl)pyridine-N,N')copper(II)
Oxidative Phosphorylation
HeLa Cells
Cervix Uteri
Oxygen Consumption
NAD
Membrane Potentials
Adenosine Diphosphate
Reactive Oxygen Species

ASJC Scopus subject areas

  • Cancer Research

Cite this

The isatin-Schiff base copper(II) complex Cu(isaepy)2 acts as delocalized lipophilic cation, yields widespread mitochondrial oxidative damage and induces AMP-activated protein kinase-dependent apoptosis. / Filomeni, Giuseppe; Piccirillo, Sara; Graziani, Ilaria; Cardaci, Simone; Da Costa Ferreira, Ana M.; Rotilio, Giuseppe; Ciriolo, Maria R.

In: Carcinogenesis, Vol. 30, No. 7, 2009, p. 1115-1124.

Research output: Contribution to journalArticle

Filomeni, Giuseppe ; Piccirillo, Sara ; Graziani, Ilaria ; Cardaci, Simone ; Da Costa Ferreira, Ana M. ; Rotilio, Giuseppe ; Ciriolo, Maria R. / The isatin-Schiff base copper(II) complex Cu(isaepy)2 acts as delocalized lipophilic cation, yields widespread mitochondrial oxidative damage and induces AMP-activated protein kinase-dependent apoptosis. In: Carcinogenesis. 2009 ; Vol. 30, No. 7. pp. 1115-1124.
@article{8c21761d4e2d4da89104cb7a91025a99,
title = "The isatin-Schiff base copper(II) complex Cu(isaepy)2 acts as delocalized lipophilic cation, yields widespread mitochondrial oxidative damage and induces AMP-activated protein kinase-dependent apoptosis",
abstract = "We previously demonstrated that Bis[(2-oxindol-3-ylimino)-2- (2-aminoethyl)pyridine-N,N′]copper(II) [Cu(isaepy)2] was an efficient inducer of the apoptotic mitochondrial pathway. Here, we deeply dissect the mechanisms underlying the ability of Cu(isaepy)2 to cause mitochondriotoxicity. In particular, we demonstrate that Cu(isaepy)2 increases NADH-dependent oxygen consumption of isolated mitochondria and that this phenomenon is associated with oxy-radical production and insensitive to adenosine diphosphate. These data indicate that Cu(isaepy)2 behaves as an uncoupler and this property is also confirmed in cell systems. Particularly, SH-SY5Y cells show: (i) an early loss of mitochondrial transmembrane potential; (ii) a decrease in the expression levels of respiratory complex components and (iii) a significant adenosine triphosphate (ATP) decrement. The causative energetic impairment mediated by Cu(isaepy)2 in apoptosis is confirmed by experiments carried out with ρ0 cells, or by glucose supplementation, where cell death is significantly inhibited. Moreover, gastric and cervix carcinoma AGS and HeLa cells, which rely most of their ATP production on oxidative phosphorylation, show a marked sensitivity toward Cu(isaepy)2. Adenosine monophosphate-activated protein kinase (AMPK), which is activated by events increasing the adenosine monophosphate:ATP ratio, is deeply involved in the apoptotic process because the overexpression of its dominant/negative form completely abolishes cell death. Upon glucose supplementation, AMPK is not activated, confirming its role as fuel-sensing enzyme that positively responds to Cu(isaepy)2 -mediated energetic impairment by committing cells to apoptosis. Overall, data obtained indicate that Cu(isaepy)2 behaves as delocalized lipophilic cation and induces mitochondrial-sited reactive oxygen species production. This event results in mitochondrial dysfunction and ATP decrease, which in turn triggers AMPK-dependent apoptosis.",
author = "Giuseppe Filomeni and Sara Piccirillo and Ilaria Graziani and Simone Cardaci and {Da Costa Ferreira}, {Ana M.} and Giuseppe Rotilio and Ciriolo, {Maria R.}",
year = "2009",
doi = "10.1093/carcin/bgp105",
language = "English",
volume = "30",
pages = "1115--1124",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "7",

}

TY - JOUR

T1 - The isatin-Schiff base copper(II) complex Cu(isaepy)2 acts as delocalized lipophilic cation, yields widespread mitochondrial oxidative damage and induces AMP-activated protein kinase-dependent apoptosis

AU - Filomeni, Giuseppe

AU - Piccirillo, Sara

AU - Graziani, Ilaria

AU - Cardaci, Simone

AU - Da Costa Ferreira, Ana M.

AU - Rotilio, Giuseppe

AU - Ciriolo, Maria R.

PY - 2009

Y1 - 2009

N2 - We previously demonstrated that Bis[(2-oxindol-3-ylimino)-2- (2-aminoethyl)pyridine-N,N′]copper(II) [Cu(isaepy)2] was an efficient inducer of the apoptotic mitochondrial pathway. Here, we deeply dissect the mechanisms underlying the ability of Cu(isaepy)2 to cause mitochondriotoxicity. In particular, we demonstrate that Cu(isaepy)2 increases NADH-dependent oxygen consumption of isolated mitochondria and that this phenomenon is associated with oxy-radical production and insensitive to adenosine diphosphate. These data indicate that Cu(isaepy)2 behaves as an uncoupler and this property is also confirmed in cell systems. Particularly, SH-SY5Y cells show: (i) an early loss of mitochondrial transmembrane potential; (ii) a decrease in the expression levels of respiratory complex components and (iii) a significant adenosine triphosphate (ATP) decrement. The causative energetic impairment mediated by Cu(isaepy)2 in apoptosis is confirmed by experiments carried out with ρ0 cells, or by glucose supplementation, where cell death is significantly inhibited. Moreover, gastric and cervix carcinoma AGS and HeLa cells, which rely most of their ATP production on oxidative phosphorylation, show a marked sensitivity toward Cu(isaepy)2. Adenosine monophosphate-activated protein kinase (AMPK), which is activated by events increasing the adenosine monophosphate:ATP ratio, is deeply involved in the apoptotic process because the overexpression of its dominant/negative form completely abolishes cell death. Upon glucose supplementation, AMPK is not activated, confirming its role as fuel-sensing enzyme that positively responds to Cu(isaepy)2 -mediated energetic impairment by committing cells to apoptosis. Overall, data obtained indicate that Cu(isaepy)2 behaves as delocalized lipophilic cation and induces mitochondrial-sited reactive oxygen species production. This event results in mitochondrial dysfunction and ATP decrease, which in turn triggers AMPK-dependent apoptosis.

AB - We previously demonstrated that Bis[(2-oxindol-3-ylimino)-2- (2-aminoethyl)pyridine-N,N′]copper(II) [Cu(isaepy)2] was an efficient inducer of the apoptotic mitochondrial pathway. Here, we deeply dissect the mechanisms underlying the ability of Cu(isaepy)2 to cause mitochondriotoxicity. In particular, we demonstrate that Cu(isaepy)2 increases NADH-dependent oxygen consumption of isolated mitochondria and that this phenomenon is associated with oxy-radical production and insensitive to adenosine diphosphate. These data indicate that Cu(isaepy)2 behaves as an uncoupler and this property is also confirmed in cell systems. Particularly, SH-SY5Y cells show: (i) an early loss of mitochondrial transmembrane potential; (ii) a decrease in the expression levels of respiratory complex components and (iii) a significant adenosine triphosphate (ATP) decrement. The causative energetic impairment mediated by Cu(isaepy)2 in apoptosis is confirmed by experiments carried out with ρ0 cells, or by glucose supplementation, where cell death is significantly inhibited. Moreover, gastric and cervix carcinoma AGS and HeLa cells, which rely most of their ATP production on oxidative phosphorylation, show a marked sensitivity toward Cu(isaepy)2. Adenosine monophosphate-activated protein kinase (AMPK), which is activated by events increasing the adenosine monophosphate:ATP ratio, is deeply involved in the apoptotic process because the overexpression of its dominant/negative form completely abolishes cell death. Upon glucose supplementation, AMPK is not activated, confirming its role as fuel-sensing enzyme that positively responds to Cu(isaepy)2 -mediated energetic impairment by committing cells to apoptosis. Overall, data obtained indicate that Cu(isaepy)2 behaves as delocalized lipophilic cation and induces mitochondrial-sited reactive oxygen species production. This event results in mitochondrial dysfunction and ATP decrease, which in turn triggers AMPK-dependent apoptosis.

UR - http://www.scopus.com/inward/record.url?scp=67650141679&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67650141679&partnerID=8YFLogxK

U2 - 10.1093/carcin/bgp105

DO - 10.1093/carcin/bgp105

M3 - Article

C2 - 19406932

AN - SCOPUS:67650141679

VL - 30

SP - 1115

EP - 1124

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 7

ER -