eriocalyxin-b and Leukemia--Myeloid--Acute

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.

Topics: Animals; Apoptosis; bcl-X Protein; Caspase 3; Cell Nucleus; Cell Proliferation; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 8; Core Binding Factor Alpha 2 Subunit; Diterpenes; Down-Regulation; Enzyme Activation; Glutathione; Hematopoietic Stem Cells; Humans; I-kappa B Proteins; Leukemia, Myeloid, Acute; MAP Kinase Signaling System; Mice; Mitochondria; NF-kappa B; NF-KappaB Inhibitor alpha; Oncogene Proteins, Fusion; Protein Processing, Post-Translational; Protein Transport; Reactive Oxygen Species; RUNX1 Translocation Partner 1 Protein; Translocation, Genetic; Tumor Necrosis Factor-alpha