| An RNA-directed nucleoside anti-metabolite, 1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine (ECyd), elicits antitumor effect via TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) downregulation. | |
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MedLine Citation:
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PMID: 20219441 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine (ECyd) is a ribose-modified nucleoside analog of cytidine with potent anticancer activity in several cancers. The main antitumor mechanism of this promising RNA-directed nucleoside anti-metabolite is efficient blockade of RNA synthesis in cancer cells. Here, we examined the therapeutic potential of this RNA-directed anti-metabolite in in vitro models of nasopharyngeal cancer (NPC). In a panel of 6 NPC cell lines, ECyd effectively inhibited cellular proliferation at nM concentrations (IC(50): approximately 13-44nM). Moreover, cisplatin-resistant NPC cells were highly sensitive to ECyd (at nM concentration). The ECyd-mediated growth inhibition was associated with G(2)/M cell cycle arrest, PARP cleavage (a hallmark of apoptosis) and Bcl-2 downregulation, indicating induction of apoptosis by ECyd in NPC cells. Unexpectedly, ECyd-induced significant downregulation of TIGAR, a newly described dual regulator of apoptosis and glycolysis. More importantly, this novel action of ECyd on TIGAR was accompanied by marked depletion of NADPH, the major reducing power critically required for cell proliferation and survival. We hypothesized that ECyd-induced TIGAR downregulation was crucially involved in the antitumor activity of ECyd. Indeed, overexpression of TIGAR was able to rescue NPC cells from ECyd-induced growth inhibition, demonstrating a novel mechanistic action of ECyd on TIGAR. We demonstrated for the first time that an RNA-directed nucleoside analog, ECyd, exerts its antitumor activity via downregulation of a novel regulator of apoptosis, TIGAR. Moreover, ECyd may represent a novel therapy for NPC. |
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Authors:
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Vivian Wai Yan Lui; Cecilia Pik Yuk Lau; Crystal Sao Fong Cheung; Kakiu Ho; Margaret Heung Ling Ng; Suk Hang Cheng; Bo Hong; Sai-Wah Tsao; Chi Man Tsang; Kenny Ieng Kit Lei; Yasundo Yamasaki; Akira Mita; Anthony T C Chan |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-02-26 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 79 ISSN: 1873-2968 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-04-12 Completed Date: 2010-05-04 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1772-80 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Cancer Drug Testing Unit, State Key Laboratory in Oncology in Southern China, Sir Y.K. Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Li Ka Shing Institute for Health Sciences, Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects Cell Cycle / drug effects Cell Line, Tumor Cell Proliferation Cytidine / analogs & derivatives*, pharmacology Dose-Response Relationship, Drug Down-Regulation* Humans Inhibitory Concentration 50 Intracellular Signaling Peptides and Proteins / genetics, metabolism* NADP / metabolism Nasopharyngeal Neoplasms / drug therapy, pathology* |
| Chemical | |
Reg. No./Substance:
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0/1-(3-C-ethynylribopentofuranosyl)cytosine; 0/C12orf5 protein, human; 0/Intracellular Signaling Peptides and Proteins; 53-59-8/NADP; 65-46-3/Cytidine |
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