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

L Wang; W-L Zhao; J-S Yan; P Liu; H-P Sun; G-B Zhou; Z-Y Weng; W-L Wu; X-Q Weng; X-J Sun; Z Chen; H-D Sun; S-J Chen

doi:10.1038/sj.cdd.4401996

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

Cell Death Differ. 2007 Feb;14(2):306-17. doi: 10.1038/sj.cdd.4401996. Epub 2006 Jun 16.

Authors

L Wang¹, W-L Zhao, J-S Yan, P Liu, H-P Sun, G-B Zhou, Z-Y Weng, W-L Wu, X-Q Weng, X-J Sun, Z Chen, H-D Sun, S-J Chen

Affiliation

¹ 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.

PMID: 16778832
DOI: 10.1038/sj.cdd.4401996

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects*
Caspase 3 / metabolism*
Cell Nucleus / drug effects
Cell Nucleus / enzymology
Cell Proliferation / drug effects
Chromosomes, Human, Pair 21 / genetics
Chromosomes, Human, Pair 8 / genetics
Core Binding Factor Alpha 2 Subunit / metabolism*
Diterpenes / chemistry
Diterpenes / pharmacology*
Down-Regulation / drug effects
Enzyme Activation / drug effects
Glutathione / metabolism
Hematopoietic Stem Cells / cytology
Hematopoietic Stem Cells / drug effects
Humans
I-kappa B Proteins / metabolism
I-kappa B Proteins / pharmacology
Leukemia, Myeloid, Acute / enzymology
Leukemia, Myeloid, Acute / metabolism*
Leukemia, Myeloid, Acute / pathology
MAP Kinase Signaling System / drug effects*
Mice
Mitochondria / drug effects
Mitochondria / enzymology
Mitochondria / ultrastructure
NF-KappaB Inhibitor alpha
NF-kappa B / antagonists & inhibitors
NF-kappa B / metabolism*
Oncogene Proteins, Fusion / metabolism*
Protein Processing, Post-Translational / drug effects
Protein Transport / drug effects
RUNX1 Translocation Partner 1 Protein
Reactive Oxygen Species / metabolism
Translocation, Genetic / drug effects
Tumor Necrosis Factor-alpha / pharmacology
bcl-X Protein / metabolism

Substances

AML1-ETO fusion protein, human
Core Binding Factor Alpha 2 Subunit
Diterpenes
I-kappa B Proteins
NF-kappa B
NFKBIA protein, human
Nfkbia protein, mouse
Oncogene Proteins, Fusion
RUNX1 Translocation Partner 1 Protein
Reactive Oxygen Species
Tumor Necrosis Factor-alpha
bcl-X Protein
eriocalyxin B
NF-KappaB Inhibitor alpha
Caspase 3
Glutathione