title: Apoptosis induction of human leukemia U937 cells by 7,8-dihydroxyflavone hydrate through modulation of the Bcl-2 family of proteins and the MAPKs signaling pathway.
abstract: 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.
authors.affiliation: Department of Pharmacy, Busan National University, Busan, Republic of Korea.
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Park
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Hwang
authors.forename: Nam Deuk
authors.initials: ND
authors.lastname: Kim
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D020813:Receptor, trkB / Q000819:agonists*; D053218:Receptors, Death Domain / Q000378:metabolism; D015398:Signal Transduction; D020298:U937 Cells
chemical_list: C485383:6,7-dihydroxyflavone; D047309:Flavones; D019253:Proto-Oncogene Proteins c-bcl-2; D053218:Receptors, Death Domain; D045304:Cytochromes c; D020813:Receptor, trkB; D020169:Caspases