Trifolin acetate-induced cell death in human leukemia cells is dependent on caspase-6 and activates the MAPK pathway

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 inhibit...

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Bibliographic Details
Published in:Apoptosis (London) 2008-05, Vol.13 (5), p.716-728
Main Authors: Torres, Fernando, Quintana, José, Díaz, Jesús G, Carmona, Armando J, Estévez, Francisco
Format: Article
Language:English
Subjects:
Amino Acid Chloromethyl Ketones - pharmacology
Apoptosis - drug effects
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cancer Research
Caspase 6 - physiology
Cell Biology
Galactosides - pharmacology
HL-60 Cells
Humans
Kaempferols - pharmacology
Leukemia
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - physiology
Mortality
Oncology
Original Paper
Oxidizing agents
Reactive Oxygen Species - metabolism
U937 Cells
Virology
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Summary: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 (ΔΨm), (ii) the activation of the mitogen-activated protein kinases (MAPKs) pathway and (iii) abrogated by the over-expression of Bcl-2 or Bcl-xL. TA-induced cell death was attenuated by inhibition of extracellular signal-regulated kinases (ERK) 1/2 with U0126 and inhibition of p38MAPK 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
1573-675X
DOI:10.1007/s10495-008-0202-0