5,7,3'-trihydroxy-3,4'-dimethoxyflavone-induced cell death in human leukemia cells is dependent on caspases and activates the MAPK pathway.

Authors:
Fernando Torres
Fernando Torres
University of Texas Southwestern Medical Center
United States
Jose Quintana
Jose Quintana
Hospital Galdakao-Usansolo (Osakidetza)-Red de Investigación en Servicios de Salud en Enfermedades Crónicas
Spain
Francisco Estevez
Francisco Estevez
Juan Canalejo Hospital
Spain

Mol Carcinog 2010 May;49(5):464-75

Department of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.

Flavonoids are polyphenolic compounds which display a vast array of biological activities and are promising anticancer agents. In this study we investigated the effect of 5,7,3'-trihydroxy-3,4'-dimethoxyflavone (THDF) on viability of nine human tumor cell lines and found that it was highly cytotoxic against leukemia cells. THDF induced G(2)-M phase cell-cycle arrest and apoptosis through a caspase-dependent mechanism involving cytochrome c release, processing of multiple caspases (caspase-3, -6, -7, and -9) and cleavage of poly(ADP-ribose) polymerase. Overexpression of the protective mitochondrial proteins Bcl-2 and Bcl-x(L) conferred partial resistance to THDF-induced apoptosis. This flavonoid induced the phosphorylation of members of the mitogen-activated protein kinases (MAPKs) family and cell death was attenuated by inhibition of c-jun N-terminal kinases/stress-activated protein kinases (JNK/SAPK) and of extracellular signal-regulated kinases (ERK) 1/2. In the present study we report that THDF-induced cell death is mediated by an intrinsic dependent apoptotic event involving mitochondria and MAPKs, and through a mechanism independent of the generation of reactive oxygen species. The results suggest that THDF could be useful in the development of novel anticancer agents.

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May 2010
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