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-κB inactivation by preventing NF-κB nuclear translocation and inducing IκBα 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.
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Abbreviations
- EriB:
-
eriocalyxin B
- AML:
-
acute myeloid leukemia
- SH:
-
sulfhydryl
- IC50:
-
fifty percents of growth inhibition concentration
- Δψm:
-
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-α:
-
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
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Acknowledgements
The authors thank Dr. Dong-Er Zhang (The Scripps Institute, La Jolla, CA, USA) for providing MigA/Etr cells and Dr. Paul B Fisher (Columbia University, NY, USA) for providing plasmid pSFFV/Bcl-2, pSFFV/Bcl-XL and pSSFV. We thank Dr. Yu-Hong Xu and Xiao-Hui Wei (Shanghai Jiao Tong University), Ting-Jun Ye, Ping Zhu, Zu-Guang Xia and Yuan-Hua Liu for technical assistance and Zhao-Jun Wen for illustrations.
This work was supported, in part, by the Chinese National Key Program for Basic Research (973:2004CB518600), the Chinese National High Tech Program (863:2002BA711A04), the National Natural Science Foundation of China (90209007 and 30400590), the Key Discipline Program of Shanghai Municipal Education Commission (Y0201), the Shanghai Commission of Science and Technology (04DZ14004 and 44107025), the Shanghai Rising Star Program (05QMX1429), the Natural Science Foundation of Yunnan Province (2004C008Z), and by the Samuel Waxman Cancer Research Foundation Laboratory.
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Wang, L., Zhao, WL., Yan, JS. et al. Eriocalyxin B induces apoptosis of t(8;21) leukemia cells through NF-κB and MAPK signaling pathways and triggers degradation of AML1-ETO oncoprotein in a caspase-3-dependent manner. Cell Death Differ 14, 306–317 (2007). https://doi.org/10.1038/sj.cdd.4401996
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DOI: https://doi.org/10.1038/sj.cdd.4401996
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