Abstract |
In the present study we demonstrated that the flavonoid derivative trifolin acetate (TA), obtained by acetylation of naturally occurring trifolin, induces apoptosis. Associated downstream signaling events were also investigated. TA-induced cell death was prevented by the non-specific caspase inhibitor z-VAD-fmk and reduced by the presence of the selective caspase inhibitors z-LEHD-fmk (caspase-9), z-DEVD-fmk (caspase-3) and z-VEID-fmk (caspase-6). The apoptotic effect of TA was associated with (i) the release of cytochrome c from mitochondria which was not accompanied by dissipation of the mitochondrial membrane potential (DeltaPsi(m)), (ii) the activation of the mitogen-activated protein kinases (MAPKs) pathway and (iii) abrogated by the over-expression of Bcl-2 or Bcl-x(L). TA-induced cell death was attenuated by inhibition of extracellular signal-regulated kinases (ERK) 1/2 with U0126 and inhibition of p38(MAPK) with SB203580. In contrast, inhibition of c-Jun NH(2)-terminal kinase (JNK) by SP600125 significantly enhanced apoptosis. Although reactive oxygen species (ROS) increased in response to TA, this did not seem to play a pivotal role in the apoptotic process since different anti-oxidants were unable to provide cell protection. The present study demonstrates that TA-induced cell death is mediated by an intrinsic-dependent apoptotic event involving mitochondria and MAPK, and through a mechanism independent of ROS generation.
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Authors | Fernando Torres, José Quintana, Jesús G Díaz, Armando J Carmona, Francisco Estévez |
Journal | Apoptosis : an international journal on programmed cell death
(Apoptosis)
Vol. 13
Issue 5
Pg. 716-28
(May 2008)
ISSN: 1573-675X [Electronic] Netherlands |
PMID | 18392682
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amino Acid Chloromethyl Ketones
- Galactosides
- Kaempferols
- Reactive Oxygen Species
- benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
- trifolin acetate
- kaempferol-3-O-galactoside
- Caspase 6
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Topics |
- Amino Acid Chloromethyl Ketones
(pharmacology)
- Apoptosis
(drug effects)
- Caspase 6
(physiology)
- Galactosides
(pharmacology)
- HL-60 Cells
- Humans
- Kaempferols
(pharmacology)
- MAP Kinase Signaling System
(drug effects, physiology)
- Reactive Oxygen Species
(metabolism)
- U937 Cells
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