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Article: 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

TitleAn 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
Authors
KeywordsAntitumor mechanism
ECyd
NADPH
NPC
TIGAR
Issue Date2010
PublisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/biochempharm
Citation
Biochemical Pharmacology, 2010, v. 79 n. 12, p. 1772-1780 How to Cite?
Abstract1-(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:∼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. © 2010 Elsevier Inc.
Persistent Identifierhttp://hdl.handle.net/10722/124469
ISSN
2015 Impact Factor: 5.091
2015 SCImago Journal Rankings: 2.263
ISI Accession Number ID
Funding AgencyGrant Number
Taiho Pharmaceutical Co., Ltd
Funding Information:

VWYL has received research support. from Taiho Pharmaceutical Co., Ltd. in this study. ATCC had received an honorarium as the advisory board member in Taiho Pharmaceutical Co., Ltd. in 2008 and has received research support from Taiho Pharmaceutical Co., Ltd. independent of this study. Result of this study was presented in parts as a poster at the AACR Annual Meeting in Denver, USA, 2009.

References

 

DC FieldValueLanguage
dc.contributor.authorLui, VWYen_HK
dc.contributor.authorLau, CPYen_HK
dc.contributor.authorCheung, CSFen_HK
dc.contributor.authorHo, Ken_HK
dc.contributor.authorNg, MHLen_HK
dc.contributor.authorCheng, SHen_HK
dc.contributor.authorHong, Ben_HK
dc.contributor.authorTsao, SWen_HK
dc.contributor.authorTsang, CMen_HK
dc.contributor.authorLei, KIKen_HK
dc.contributor.authorYamasaki, Yen_HK
dc.contributor.authorMita, Aen_HK
dc.contributor.authorChan, ATCen_HK
dc.date.accessioned2010-10-31T10:36:09Z-
dc.date.available2010-10-31T10:36:09Z-
dc.date.issued2010en_HK
dc.identifier.citationBiochemical Pharmacology, 2010, v. 79 n. 12, p. 1772-1780en_HK
dc.identifier.issn0006-2952en_HK
dc.identifier.urihttp://hdl.handle.net/10722/124469-
dc.description.abstract1-(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:∼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. © 2010 Elsevier Inc.en_HK
dc.languageengen_HK
dc.publisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/biochempharmen_HK
dc.relation.ispartofBiochemical Pharmacologyen_HK
dc.subjectAntitumor mechanismen_HK
dc.subjectECyden_HK
dc.subjectNADPHen_HK
dc.subjectNPCen_HK
dc.subjectTIGARen_HK
dc.subject.meshApoptosis - drug effects-
dc.subject.meshCytidine - analogs and derivatives - pharmacology-
dc.subject.meshDown-Regulation-
dc.subject.meshIntracellular Signaling Peptides and Proteins - genetics - metabolism-
dc.subject.meshNasopharyngeal Neoplasms - drug therapy - pathology-
dc.titleAn 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) downregulationen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0006-2952&volume=79&issue=12&spage=1772&epage=1780&date=2010&atitle=An+RNA-directed+nucleoside+anti-metabolite,+1-(3-C-ethynyl-beta-D-ribopentofuranosyl)+cytosine+(ECyd),+elicits+antitumor+effect+via+TP53-induced Glycolysis+and+Apoptosis+Regulator+(TIGAR)+downregulationen_HK
dc.identifier.emailTsao, SW:gswtsao@hkucc.hku.hken_HK
dc.identifier.authorityTsao, SW=rp00399en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.bcp.2010.02.012en_HK
dc.identifier.pmid20219441-
dc.identifier.scopuseid_2-s2.0-77951298866en_HK
dc.identifier.hkuros182818en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77951298866&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume79en_HK
dc.identifier.issue12en_HK
dc.identifier.spage1772en_HK
dc.identifier.epage1780en_HK
dc.identifier.isiWOS:000276986000008-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLui, VWY=7004231347en_HK
dc.identifier.scopusauthoridLau, CPY=36608195100en_HK
dc.identifier.scopusauthoridCheung, CSF=35080091300en_HK
dc.identifier.scopusauthoridHo, K=34971221500en_HK
dc.identifier.scopusauthoridNg, MHL=35292609300en_HK
dc.identifier.scopusauthoridCheng, SH=7404681588en_HK
dc.identifier.scopusauthoridHong, B=7202125896en_HK
dc.identifier.scopusauthoridTsao, SW=7102813116en_HK
dc.identifier.scopusauthoridTsang, CM=24831236400en_HK
dc.identifier.scopusauthoridLei, KIK=7102208067en_HK
dc.identifier.scopusauthoridYamasaki, Y=7202564107en_HK
dc.identifier.scopusauthoridMita, A=36059672600en_HK
dc.identifier.scopusauthoridChan, ATC=13404833700en_HK
dc.identifier.citeulike6864463-

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