title: 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.
abstract: 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.
authors.affiliation: 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.
authors.forename: Vivian Wai Yan
authors.initials: VW
authors.lastname: Lui
authors.forename: Cecilia Pik Yuk
authors.initials: CP
authors.lastname: Lau
authors.forename: Crystal Sao Fong
authors.initials: CS
authors.lastname: Cheung
authors.forename: Kakiu
authors.initials: K
authors.lastname: Ho
authors.forename: Margaret Heung Ling
authors.initials: MH
authors.lastname: Ng
authors.forename: Suk Hang
authors.initials: SH
authors.lastname: Cheng
authors.forename: Bo
authors.initials: B
authors.lastname: Hong
authors.forename: Sai-Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Chi Man
authors.initials: CM
authors.lastname: Tsang
authors.forename: Kenny Ieng Kit
authors.initials: KI
authors.lastname: Lei
authors.forename: Yasundo
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: Akira
authors.initials: A
authors.lastname: Mita
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010744:Phosphoric Monoester Hydrolases
chemical_list: C103084:1-(3-C-ethynylribopentofuranosyl)cytosine; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009249:NADP; D003562:Cytidine; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human