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Title: Trifolin acetate-induced cell death in human leukemia cells is dependent on caspase-6 and activates the MAPK pathway
Authors: Torres, Fernando
Quintana, Jose 
Díaz, Jesús G.
Carmona, Armando J.
Estévez, Francisco 
Keywords: N-Terminal-Kinase
Jun Nh2-Terminal Kinase
Induced Apoptosis
Cytochrome-C, et al
Issue Date: 2008
Publisher: 1360-8185
Project: Nuevos Compuestos Antileucémicos 
Journal: Apoptosis : an international journal on programmed cell death 
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 (Delta Psi(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 NH2-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.
ISSN: 1360-8185
DOI: 10.1007/s10495-008-0202-0
Source: Apoptosis[ISSN 1360-8185],v. 13, p. 716-728
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