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Carcinogenesis Advance Access published online on June 4, 2007
Carcinogenesis, doi:10.1093/carcin/bgm131
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Acetyl derivative of quercetin 3-methyl ether–induced cell death in human leukemia cells is amplified by the inhibition of ERK

Sara Rubio1, José Quintana1, José Luis Eiroa2, Jorge Triana2 and Francisco Estévez1,*

1 Department of Biochemistry, University of Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria, Spain
2 Department of Chemistry, I.C.I.C., University of Las Palmas de Gran Canaria, Campus Universitario de Tafira, 35017 Las Palmas de Gran Canaria, Spain

* Corresponding author. Tel.: +34-928-451443; fax: +34-928-451441E-mail address: festevez{at}dbbf.ulpgc.es (F.Estévez)

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-{gamma}-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: 1) mediated by caspase activation, since it was prevented by the non-specific caspase inhibitor z-VAD-fmk, 2) associated with cytochrome c release, and 3) triggered in Bcl-2-overexpressing 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 NH2-terminal kinase (JNK), p38MAPK and extracellular signal-regulated kinases (ERK) 1/2. Inhibition of JNK by SP600125 and of p38MAPK 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 leukaemia HL-60 cells towards QD.

Received January 24, 2007; revised May 22, 2007; accepted May 23, 2007.


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