5,7,3 '-Trihydroxy-3,4 '-Dimethoxyflavone-Induced Cell Death in Human Leukemia Cells Is Dependent on Caspases and Activates the MAPK Pathway

作者：Torres Fernando; Quintana Jose; Estevez Francisco^*

来源：Molecular Carcinogenesis, 2010, 49(5): 464-475.

DOI：10.1002/mc.20619

• apoptosis
• flavonoids
• cell-cycle arrest
• mitogen-activated protein kinases
• c-jun N-terminal kinases
• extracellular signal-regulated kinases

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.

• 出版日期2010-5