TY - JOUR
T1 - Trifolin acetate-induced cell death in human leukemia cells is dependent on caspase-6 and activates the MAPK pathway
AU - Torres, Fernando
AU - Quintana, José
AU - Díaz, Jesús G.
AU - Carmona, Armando J.
AU - Estévez, Francisco
PY - 2008/5
Y1 - 2008/5
N2 - 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 (ΔΨ
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.
AB - 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 (ΔΨ
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.
KW - Apoptosis
KW - Extracellular signal-regulated kinases
KW - Flavonoids
KW - Mitogen-activated protein kinase
KW - p38
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UR - http://www.scopus.com/inward/citedby.url?scp=42149184054&partnerID=8YFLogxK
U2 - 10.1007/s10495-008-0202-0
DO - 10.1007/s10495-008-0202-0
M3 - Article
C2 - 18392682
AN - SCOPUS:42149184054
VL - 13
SP - 716
EP - 728
JO - Apoptosis : an international journal on programmed cell death
JF - Apoptosis : an international journal on programmed cell death
SN - 1360-8185
IS - 5
ER -