| Induction of apoptosis by esculetin in human leukemia U937 cells: roles of Bcl-2 and extracellular-regulated kinase signaling. | |
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MedLine Citation:
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PMID: 19786087 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In the present study, we reported that apoptosis induced by esculetin, a phenolic compound with apoptotic activity in cancer cells, was markedly blocked by Bcl-2-overexpression, but restored by HA14-1, a small-molecule Bcl-2 inhibitor, in human leukemic U937 cells. The combined use of esculetin and HA14-1 effectively induced Bid cleavage and loss of mitochondrial membrane potential (MMP, Deltapsi(m)) leading to the activation of caspases and cleavage of poly(ADP-ribose) polymerase (PARP) in Bcl-2-overexpressing (U937/Bcl-2) cells. Combined treatment with esculetin and HA14-1 upregulated the expression of death receptor 4 (DR4), and activation of extracellular-regulated kinase (ERK) in a time-dependent manner. In addition, esculetin and HA14-1-mediated apoptosis was reduced by ERK inhibitors through inhibition of DR4 expression, suggesting that the synergistic effect was at least partially mediated through ERK-dependent induction of DR4 expression. The results indicate that HA14-1-induced reversal of the anti-apoptotic effect of Bcl-2 confers apoptosis sensitivity to esculetin by a mitochondrial amplification step and through the ERK-dependent induction of DR4 expression in U937/Bcl-2 cells. Thus, HA14-1 reversal of Bcl-2-mediated esculetin resistance suggests a novel strategy for increasing esculetin sensitivity in Bcl-2-overexpressing leukemia cells. |
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Authors:
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Cheol Park; Cheng-Yun Jin; Hyun Ju Kwon; Hye Jin Hwang; Gi-Young Kim; Il Whan Choi; Taeg Kyu Kwon; Byung-Woo Kim; Wun-Jae Kim; Yung Hyun Choi |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-09-26 |
Journal Detail:
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Title: Toxicology in vitro : an international journal published in association with BIBRA Volume: 24 ISSN: 1879-3177 ISO Abbreviation: Toxicol In Vitro Publication Date: 2010 Mar |
Date Detail:
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Created Date: 2010-02-22 Completed Date: 2010-06-02 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8712158 Medline TA: Toxicol In Vitro Country: England |
Other Details:
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Languages: eng Pagination: 486-94 Citation Subset: IM |
Copyright Information:
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Copyright (c) 2009 Elsevier Ltd. All rights reserved. |
Affiliation:
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Blue-Bio Industry Regional Innovation Center, Dongeui University, Busan 614-714, Republic of Korea. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects* Benzopyrans / pharmacology Dose-Response Relationship, Drug Enzyme Inhibitors Extracellular Signal-Regulated MAP Kinases / genetics, metabolism* Gene Expression Regulation / drug effects Genes, bcl-2 / genetics, physiology* Humans Nitriles / pharmacology U937 Cells Umbelliferones / toxicity* |
| Chemical | |
Reg. No./Substance:
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0/Benzopyrans; 0/Enzyme Inhibitors; 0/Nitriles; 0/Umbelliferones; 0/ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; 305-01-1/esculetin; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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