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: 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
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 14 Issue 2 Pg. 306-17 (Feb 2007) ISSN: 1350-9047 [Print] England
• PMID: 16778832 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Animals
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Nucleus (drug effects, enzymology)
• Cell Proliferation (drug effects)
• Chromosomes, Human, Pair 21 (genetics)
• Chromosomes, Human, Pair 8 (genetics)
• Core Binding Factor Alpha 2 Subunit (metabolism)
• Diterpenes (chemistry, pharmacology)
• Down-Regulation (drug effects)
• Enzyme Activation (drug effects)
• Glutathione (metabolism)
• Hematopoietic Stem Cells (cytology, drug effects)
• Humans
• I-kappa B Proteins (metabolism, pharmacology)
• Leukemia, Myeloid, Acute (enzymology, metabolism, pathology)
• MAP Kinase Signaling System (drug effects)
• Mice
• Mitochondria (drug effects, enzymology, ultrastructure)
• NF-KappaB Inhibitor alpha
• NF-kappa B (antagonists & inhibitors, 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)