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Article: The impact of hypoxic treatment on the expression of phosphoglycerate kinase and the cytotoxicity of troxacitabine and gemcitabine
Title | The impact of hypoxic treatment on the expression of phosphoglycerate kinase and the cytotoxicity of troxacitabine and gemcitabine |
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Authors | |
Issue Date | 2007 |
Publisher | American Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org |
Citation | Molecular Pharmacology, 2007, v. 72 n. 3, p. 536-544 How to Cite? |
Abstract | β-L-Dioxolane-cytidine (L-OddC, Troxacitabine, BCH-4556), a novel L-configuration deoxycytidine analog, is under clinical trials for treating cancer. The cytotoxicity of L-OddC is dependent on the amount of the triphosphate form (L-OddCTP) in nuclear DNA. Phosphoglycerate kinase (PGK), a downstream protein of hypoxia-inducible-factor-1α (HIF-1α), is responsible for the phosphorylation of the diphosphate to the triphosphate of L-OddC. In this study, we studied the impact of hypoxia on the metabolism and the cytotoxicity of L-OddC and β-D-2′,2′-difluorodeoxycytidine (dFdC) in several human tumor cell lines including HepG2, Hep3B, A673, Panc-1, and RKO. Hypoxic treatment induced the protein expression of PGK 3-fold but had no effect on the protein expression of APE-1, dCK, CMPK, and nM23 H1. Hypoxic treatment increased L-OddCTP formation and incorporation of L-OddC into DNA, but it decreased the uptake and incorporation of dFdC, which correlated with the reduction of hENT1, hENT2, and hCNT2 expression. Using a clonogenic assay, hypoxic treatment of cells made them 2- to 3-fold more susceptible to L-OddC but not to dFdC after exposure to drugs for one generation. Dimethyloxallyl glycine enhanced the cytotoxicity of L-OddC but not dFdC in Panc-1 cells under normoxic conditions. Overexpression or down-regulation of PGK using transient transfection of pcDNA5-PGK or inducible shRNA in RKO cells affected the cytotoxicity of L-OddC but not that of dFdC. The knockdown of HIF-1α in inducible shRNA in RKO cells reduced the cytotoxicity of L-OddC but not dFdC under hypoxic conditions. In conclusion, hypoxia is an important factor that may potentiate the activity of L-OddC. Copyright © 2007 The American Society for Pharmacology and Experimental Therapeutics. |
Persistent Identifier | http://hdl.handle.net/10722/168139 |
ISSN | 2023 Impact Factor: 3.2 2023 SCImago Journal Rankings: 1.038 |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
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dc.contributor.author | Lam, W | en_US |
dc.contributor.author | Leung, CH | en_US |
dc.contributor.author | Bussom, S | en_US |
dc.contributor.author | Cheng, YC | en_US |
dc.date.accessioned | 2012-10-08T03:15:34Z | - |
dc.date.available | 2012-10-08T03:15:34Z | - |
dc.date.issued | 2007 | en_US |
dc.identifier.citation | Molecular Pharmacology, 2007, v. 72 n. 3, p. 536-544 | en_US |
dc.identifier.issn | 0026-895X | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/168139 | - |
dc.description.abstract | β-L-Dioxolane-cytidine (L-OddC, Troxacitabine, BCH-4556), a novel L-configuration deoxycytidine analog, is under clinical trials for treating cancer. The cytotoxicity of L-OddC is dependent on the amount of the triphosphate form (L-OddCTP) in nuclear DNA. Phosphoglycerate kinase (PGK), a downstream protein of hypoxia-inducible-factor-1α (HIF-1α), is responsible for the phosphorylation of the diphosphate to the triphosphate of L-OddC. In this study, we studied the impact of hypoxia on the metabolism and the cytotoxicity of L-OddC and β-D-2′,2′-difluorodeoxycytidine (dFdC) in several human tumor cell lines including HepG2, Hep3B, A673, Panc-1, and RKO. Hypoxic treatment induced the protein expression of PGK 3-fold but had no effect on the protein expression of APE-1, dCK, CMPK, and nM23 H1. Hypoxic treatment increased L-OddCTP formation and incorporation of L-OddC into DNA, but it decreased the uptake and incorporation of dFdC, which correlated with the reduction of hENT1, hENT2, and hCNT2 expression. Using a clonogenic assay, hypoxic treatment of cells made them 2- to 3-fold more susceptible to L-OddC but not to dFdC after exposure to drugs for one generation. Dimethyloxallyl glycine enhanced the cytotoxicity of L-OddC but not dFdC in Panc-1 cells under normoxic conditions. Overexpression or down-regulation of PGK using transient transfection of pcDNA5-PGK or inducible shRNA in RKO cells affected the cytotoxicity of L-OddC but not that of dFdC. The knockdown of HIF-1α in inducible shRNA in RKO cells reduced the cytotoxicity of L-OddC but not dFdC under hypoxic conditions. In conclusion, hypoxia is an important factor that may potentiate the activity of L-OddC. Copyright © 2007 The American Society for Pharmacology and Experimental Therapeutics. | en_US |
dc.language | eng | en_US |
dc.publisher | American Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org | en_US |
dc.relation.ispartof | Molecular Pharmacology | en_US |
dc.subject.mesh | Antimetabolites, Antineoplastic - Toxicity | en_US |
dc.subject.mesh | Antineoplastic Agents - Toxicity | en_US |
dc.subject.mesh | Carcinoma - Pathology | en_US |
dc.subject.mesh | Carcinoma, Hepatocellular - Pathology | en_US |
dc.subject.mesh | Cell Hypoxia | en_US |
dc.subject.mesh | Cell Line, Tumor | en_US |
dc.subject.mesh | Colonic Neoplasms - Pathology | en_US |
dc.subject.mesh | Cytosine - Analogs & Derivatives - Toxicity | en_US |
dc.subject.mesh | Dna-(Apurinic Or Apyrimidinic Site) Lyase - Metabolism | en_US |
dc.subject.mesh | Deoxycytidine - Analogs & Derivatives - Toxicity | en_US |
dc.subject.mesh | Dioxolanes - Toxicity | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Liver Neoplasms - Pathology | en_US |
dc.subject.mesh | Pancreatic Neoplasms - Pathology | en_US |
dc.subject.mesh | Phosphoglycerate Kinase - Metabolism | en_US |
dc.subject.mesh | Rhabdomyosarcoma - Pathology | en_US |
dc.title | The impact of hypoxic treatment on the expression of phosphoglycerate kinase and the cytotoxicity of troxacitabine and gemcitabine | en_US |
dc.type | Article | en_US |
dc.identifier.email | Leung, CH:duncanl@hkucc.hku.hk | en_US |
dc.identifier.authority | Leung, CH=rp00730 | en_US |
dc.description.nature | link_to_subscribed_fulltext | en_US |
dc.identifier.doi | 10.1124/mol.106.033472 | en_US |
dc.identifier.pmid | 17565005 | - |
dc.identifier.scopus | eid_2-s2.0-34548313707 | en_US |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-34548313707&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 72 | en_US |
dc.identifier.issue | 3 | en_US |
dc.identifier.spage | 536 | en_US |
dc.identifier.epage | 544 | en_US |
dc.identifier.isi | WOS:000248976400006 | - |
dc.publisher.place | United States | en_US |
dc.identifier.scopusauthorid | Lam, W=7203021943 | en_US |
dc.identifier.scopusauthorid | Leung, CH=7402612570 | en_US |
dc.identifier.scopusauthorid | Bussom, S=16743813200 | en_US |
dc.identifier.scopusauthorid | Cheng, YC=36041844200 | en_US |
dc.identifier.issnl | 0026-895X | - |