Original Paper
Cell Death and Differentiation (2007) 14, 306–317. doi:10.1038/sj.cdd.4401996; published online 16 June 2006
Eriocalyxin B induces apoptosis of t(8;21) leukemia cells through NF-
B and MAPK signaling pathways and triggers degradation of AML1-ETO oncoprotein in a caspase-3-dependent manner
Edited by R De Maria
L Wang1,3, W-L Zhao1,3, J-S Yan1,3, P Liu1,3, H-P Sun1, G-B Zhou1, Z-Y Weng2, W-L Wu1, X-Q Weng1, X-J Sun1, Z Chen1, H-D Sun2 and S-J Chen1
- 1State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Institute of Health Science, Shanghai Institutes for Biological Sciences and Graduate School, Chinese Academy of Sciences and School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
- 2Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, Yunnan, China
Correspondence: Z Chen, E-mail: zchen@stn.sh.cn; H-D Sun, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, Yunnan, China. E-mail: hdsun@mail.kib.ac.cn; S-J Chen, State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Rui Jin Er Road, Shanghai 200025, China. Tel: +86 21 64377859; Fax: +86 21 64743206; E-mail: sjchen@stn.sh.cn
3These authors equally contributed to this work
Received 25 November 2005; Revised 2 May 2006; Accepted 16 May 2006; Published online 16 June 2006.
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-
B inactivation by preventing NF-B nuclear translocation and inducing IB
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.
Keywords:
eriocalyxin B, acute myeloid leukemia, apoptosis, NF-B, MAPK, AML1-ETO
Abbreviations:
EriB, eriocalyxin B; AML, acute myeloid leukemia; SH, sulfhydryl; IC50, fifty percents of growth inhibition concentration; 
m, mitochondrial membrane potential; p-ERK1/2, phosphorylated form of ERK1/2; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PI, propidium iodide; Rh123, rhodamine 123; DCFH-DA, dichlorofluorescein diacetate; TNF-, tumor necrosis factor alpha; DTT, dithiothreitol; PARP, poly (ADP-ribose) polymerase; ROS, reactive oxygen species; GSH, glutathione; OS, overall survival; NP-40, Nonidet P-40; HEPES, N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid; RT-PCR, reverse transcription PCR; OD, optical density
