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Eriocalyxin B induces apoptosis in lymphoma cells through multiple cellular signaling pathways.
- Source :
-
Experimental hematology [Exp Hematol] 2010 Mar; Vol. 38 (3), pp. 191-201. Date of Electronic Publication: 2010 Jan 04. - Publication Year :
- 2010
-
Abstract
- Objective: Eriocalyxin B (EriB) is a natural diterpenoid purified from Isodon eriocalyx var. laxiflora and possesses strong antileukemic activity. In this study, we further investigated its effect and mechanism of action in human lymphoma.<br />Materials and Methods: In vitro, a series of B- and T-lymphoma cells were treated with EriB. Cell apoptosis was analyzed using flow cytometric assay. Expression of proteins related to apoptosis and cell signal transduction were assessed using Western blot. In vivo antitumor activity of EriB was examined in murine xenograft B- and T-lymphoma models, with in situ cell apoptosis detected by terminal deoxytransferase-catalyzed DNA nick-end labeling assay.<br />Results: EriB significantly inhibited lymphoma cell proliferation and induced apoptosis in association with caspase activation. Antiapoptotic Bcl-2 family members Bcl-2 and Bcl-xL were downregulated, with proapoptotic member Bax stable or upregulated, resulting in reduced Bcl-2/Bax and Bcl-xL/Bax ratios. Meanwhile, multiple signal transduction pathways were involved in lymphoma cell apoptosis in response to EriB, including inhibition of nuclear factor (NF)-kappaB and AKT pathways, and the activation of extracellular signal-related kinase (ERK) pathway. AKT inactivation was related to increased expression of cyclin-dependent kinase inhibitor P21, decreased expression of antiapoptotic phosphorylated form of Bad, and NF-kappaB activator IkappaB kinase alpha/beta. ERK activation corresponded to reactive oxygen species production and could be blocked by antioxidant dithiothreitol. In murine xenograft lymphoma models, EriB remarkably inhibited tumor growth and induced in situ tumor cell apoptosis.<br />Conclusion: These findings broaden the value of EriB as a promising candidate targeting apoptosis cascade in treatment of hematological malignancies.<br /> (Copyright 2010 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Blotting, Western
Caspase 3 metabolism
Cell Line, Tumor
Cell Survival drug effects
Dose-Response Relationship, Drug
Enzyme Activation drug effects
Extracellular Signal-Regulated MAP Kinases
Flow Cytometry
Humans
In Situ Nick-End Labeling
Jurkat Cells
Lymphoma metabolism
Lymphoma pathology
Mice
Mice, Nude
NF-kappa B antagonists & inhibitors
NF-kappa B metabolism
Proto-Oncogene Proteins c-akt metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
Tumor Burden drug effects
Xenograft Model Antitumor Assays
bcl-2-Associated X Protein metabolism
bcl-X Protein metabolism
Apoptosis drug effects
Diterpenes pharmacology
Lymphoma drug therapy
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2399
- Volume :
- 38
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Experimental hematology
- Publication Type :
- Academic Journal
- Accession number :
- 20045442
- Full Text :
- https://doi.org/10.1016/j.exphem.2009.12.005