6-7-dihydroxyflavone and Leukemia

The present study investigated possible mechanisms of apoptosis induction of U937 human leukemic cells by 7,8-dihydroxyflavone hydrate (7,8-DHF), a member of the flavonoid family and a recently identified tyrosine kinase receptor B (TrkB) agonist. 7,8-DHF treatment of U937 cells resulted in inhibition of growth and induction of apoptosis as measured by MTT assay, fluorescence microscopy, DNA fragmentation, and flow cytometry analysis. 7,8-DHF-induced apoptosis in U937 cells was correlated with the up-regulation of death receptor related protein levels and down-regulation of anti-apoptotic IAP family proteins. The increase in apoptosis was also associated with proteolytic activation of caspases, Bid cleavage, insertion of pro-apoptotic Bax into the mitochondria and release of cytochrome c from mitochondria to cytosol. Furthermore, it was found that Bcl-2 overexpression markedly protected U937 cells from 7,8-DHF-induced apoptosis by restoring activation of caspases. In addition, 7,8-DHF treatment effectively activated the mitogen-activated protein kinases (MAPK), and inhibitors of extracellular-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), but not p38 MAPK, which significantly reduced 7,8-DHF-induced apoptosis. Taken together, our results indicate that the JNK and ERK pathways, and modulation of Bcl-2 family proteins were key regulators of apoptosis in response to 7,8-DHF in U937 cells.

Topics: Apoptosis; Caspases; Cell Proliferation; Cytochromes c; Flavones; Humans; Leukemia; MAP Kinase Signaling System; Proto-Oncogene Proteins c-bcl-2; Receptor, trkB; Receptors, Death Domain; Signal Transduction; U937 Cells