Carcinogenesis Advance Access originally published online on June 4, 2007
Carcinogenesis 2007 28(10):2105-2113; doi:10.1093/carcin/bgm131
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Acetyl derivative of quercetin 3-methyl ether-induced cell death in human leukemia cells is amplified by the inhibition of ERK
Department of Biochemistry, University of Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria, Spain
1 Department of Chemistry, Instituto Canario de Investigación del Cáncer, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira, 35017 Las Palmas de Gran Canaria, Spain
* To whom correspondence should be addressed. Tel: +34 928 451443; Fax: +34 928 451441; Email: festevez{at}dbbf.ulpgc.es
Flavonoids are polyphenolic compounds that are ubiquitously in plants and display a vast array of biological activities. Here we have studied the effect of the phenylbenzo-
-pyrone-derivative quercetin 3-methyl ether tetracetate (QD), obtained by acetylation of the natural product quercetin 3-methyl ether, on cell viability of human leukemia HL-60 and U937 cell lines. The results show that QD was cytotoxic and induced G2–M phase cell cycle arrest on both cell lines and it was a potent apoptotic inducer on HL-60 cells. QD-induced apoptosis is (i) mediated by caspase activation, since it was prevented by the non-specific caspase inhibitor z-VAD-fmk, (ii) associated with cytochrome c release and (iii) triggered in Bcl-2 over-expressing U937 cells. The treatment of HL-60 and U937 cells with QD also induces the activation of the mitogen-activated protein kinases (MAPKs) pathway, including c-Jun N-terminal kinase, p38 mitogen-activated protein kinase and extracellular signal-regulated kinases (ERK) 1/2. Inhibition of c-Jun N-terminal kinase by SP600125 and of p38 mitogen-activated protein kinase by SB203580 had no influence on QD-mediated apoptosis. In contrast, inhibition of ERK1/2 with the pharmacologic inhibitors U0126 or PD98059, together with QD, resulted in an important enhancement of apoptosis. Cells are sensitized to QD-mediated apoptosis after blocking ERK1/2, which suggests that inhibition of this pathway is a valuable strategy to increase the sensitivity of human leukemia HL-60 cells toward QD.
Abbreviations: ara-C, 1-ß-D-arabinofuranosylcytosine; ERK, extracellular signal-regulated kinase; IC50, 50% inhibition of cell growth; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated extracellular kinase; PARP, poly (ADP-ribose) polymerase; PBMC, peripheral blood mononuclear cell; p38MAPK, p38 mitogen-activated protein kinase; ROS, reactive oxygen species; SAPK, stress-activated protein kinase; QD, tetracetyl derivative of quercetin 3-methyl ether
Received January 24, 2007; revised May 22, 2007; accepted May 23, 2007.