5,7,3'-trihydroxy-3,4'-dimethoxyflavone-induced cell death in human leukemia cells is dependent on caspases and activates the MAPK pathway.
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.
Torres
Fernando
F
Department of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
Quintana
José
J
Estévez
Francisco
F
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D002455:Cell Division; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D047309:Flavones / Q000494:pharmacology*; D005434:Flow Cytometry; D016195:G2 Phase; D006801:Humans; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000473:pathology*; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology; D020935:MAP Kinase Signaling System
C549753:5,7,3'-trihydroxy-3,4'-dimethoxyflavone; D016588:Anticarcinogenic Agents; D047309:Flavones; D020169:Caspases