title: Eriocalyxin B induces apoptosis of t(8;21) leukemia cells through NF-kappaB and MAPK signaling pathways and triggers degradation of AML1-ETO oncoprotein in a caspase-3-dependent manner.
abstract: Diterpenoids isolated from Labiatae family herbs have strong antitumor activities with low toxicity. In this study, Eriocalyxin B (EriB), a diterpenoid extracted from Isodon eriocalyx, was tested on human leukemia/lymphoma cells and murine leukemia models. Acute myeloid leukemia cell line Kasumi-1 was most sensitive to EriB. Significant apoptosis was observed, concomitant with Bcl-2/Bcl-XL downregulation, mitochondrial instability and caspase-3 activation. AML1-ETO oncoprotein was degraded in parallel to caspase-3 activation. EriB-mediated apoptosis was associated with NF-kappaB inactivation by preventing NF-kappaB nuclear translocation and inducing IkappaBalpha cleavage, and disturbance of MAPK pathway by downregulating ERK1/2 phosphorylation and activating AP-1. Without affecting normal hematopoietic progenitor cells proliferation, EriB was effective on primary t(8;21) leukemia blasts and caused AML1-ETO degradation. In murine t(8;21) leukemia models, EriB remarkably prolonged the survival time or decreased the xenograft tumor size. Together, EriB might be a potential treatment for t(8;21) leukemia by targeting AML1-ETO oncoprotein and activating apoptosis pathways.
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Chinese Academy of Sciences and School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: W-L
authors.initials: WL
authors.lastname: Zhao
authors.forename: J-S
authors.initials: JS
authors.lastname: Yan
authors.forename: P
authors.initials: P
authors.lastname: Liu
authors.forename: H-P
authors.initials: HP
authors.lastname: Sun
authors.forename: G-B
authors.initials: GB
authors.lastname: Zhou
authors.forename: Z-Y
authors.initials: ZY
authors.lastname: Weng
authors.forename: W-L
authors.initials: WL
authors.lastname: Wu
authors.forename: X-Q
authors.initials: XQ
authors.lastname: Weng
authors.forename: X-J
authors.initials: XJ
authors.lastname: Sun
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: H-D
authors.initials: HD
authors.lastname: Sun
authors.forename: S-J
authors.initials: SJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D049109:Cell Proliferation / Q000187:drug effects; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D000075142:RUNX1 Translocation Partner 1 Protein; D017382:Reactive Oxygen Species / Q000378:metabolism; D014178:Translocation, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D004224:Diterpenes; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; C516552:eriocalyxin B; D000072000:NF-KappaB Inhibitor alpha; D053148:Caspase 3; D005978:Glutathione