title: Apigenin induces apoptosis in human leukemia cells and exhibits anti-leukemic activity in vivo.
abstract: In this study, we investigated the functional role of Akt and c-jun-NH(2)-kinase (JNK) signaling cascades in apigenin-induced apoptosis in U937 human leukemia cells and anti-leukemic activity of apigenin in vivo. Apigenin induced apoptosis by inactivation of Akt with a concomitant activation of JNK, Mcl-1 and Bcl-2 downregulation, cytochrome c release from mitochondria, and activation of caspases. Constitutively active myristolated Akt prevented apigenin-induced JNK, caspase activation, and apoptosis. Conversely, LY294002 and a dominant-negative construct of Akt potentiated apigenin-induced apoptosis in leukemia cells. Interruption of the JNK pathway showed marked reduction in apigenin-induced caspase activation and apoptosis in leukemia cells. Furthermore, in vivo administration of apigenin resulted in attenuation of tumor growth in U937 xenografts accompanied by inactivation of Akt and activation of JNK. Attenuation of tumor growth in U937 xenografts by apigenin raises the possibility that apigenin may have clinical implications and can be further tested for incorporating in leukemia treatment regimens.
authors.affiliation: Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Budhraja
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Young-Ok
authors.initials: YO
authors.lastname: Son
authors.forename: Senping
authors.initials: S
authors.lastname: Cheng
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Songze
authors.initials: S
authors.lastname: Ding
authors.forename: Andrew
authors.initials: A
authors.lastname: Hitron
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
mesh_terms: D000818:Animals; D047310:Apigenin / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D002867:Chromones; C579094:Mcl1 protein, mouse; D009025:Morpholines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D047310:Apigenin; D045304:Cytochromes c; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases
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