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Article: The impact of hypoxic treatment on the expression of phosphoglycerate kinase and the cytotoxicity of troxacitabine and gemcitabine

TitleThe impact of hypoxic treatment on the expression of phosphoglycerate kinase and the cytotoxicity of troxacitabine and gemcitabine
Authors
Issue Date2007
PublisherAmerican 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?
Abstractβ-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 Identifierhttp://hdl.handle.net/10722/168139
ISSN
2015 Impact Factor: 3.931
2015 SCImago Journal Rankings: 2.047
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLam, Wen_US
dc.contributor.authorLeung, CHen_US
dc.contributor.authorBussom, Sen_US
dc.contributor.authorCheng, YCen_US
dc.date.accessioned2012-10-08T03:15:34Z-
dc.date.available2012-10-08T03:15:34Z-
dc.date.issued2007en_US
dc.identifier.citationMolecular Pharmacology, 2007, v. 72 n. 3, p. 536-544en_US
dc.identifier.issn0026-895Xen_US
dc.identifier.urihttp://hdl.handle.net/10722/168139-
dc.description.abstractβ-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.languageengen_US
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.orgen_US
dc.relation.ispartofMolecular Pharmacologyen_US
dc.subject.meshAntimetabolites, Antineoplastic - Toxicityen_US
dc.subject.meshAntineoplastic Agents - Toxicityen_US
dc.subject.meshCarcinoma - Pathologyen_US
dc.subject.meshCarcinoma, Hepatocellular - Pathologyen_US
dc.subject.meshCell Hypoxiaen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshColonic Neoplasms - Pathologyen_US
dc.subject.meshCytosine - Analogs & Derivatives - Toxicityen_US
dc.subject.meshDna-(Apurinic Or Apyrimidinic Site) Lyase - Metabolismen_US
dc.subject.meshDeoxycytidine - Analogs & Derivatives - Toxicityen_US
dc.subject.meshDioxolanes - Toxicityen_US
dc.subject.meshHumansen_US
dc.subject.meshLiver Neoplasms - Pathologyen_US
dc.subject.meshPancreatic Neoplasms - Pathologyen_US
dc.subject.meshPhosphoglycerate Kinase - Metabolismen_US
dc.subject.meshRhabdomyosarcoma - Pathologyen_US
dc.titleThe impact of hypoxic treatment on the expression of phosphoglycerate kinase and the cytotoxicity of troxacitabine and gemcitabineen_US
dc.typeArticleen_US
dc.identifier.emailLeung, CH:duncanl@hkucc.hku.hken_US
dc.identifier.authorityLeung, CH=rp00730en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1124/mol.106.033472en_US
dc.identifier.pmid17565005-
dc.identifier.scopuseid_2-s2.0-34548313707en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-34548313707&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume72en_US
dc.identifier.issue3en_US
dc.identifier.spage536en_US
dc.identifier.epage544en_US
dc.identifier.isiWOS:000248976400006-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridLam, W=7203021943en_US
dc.identifier.scopusauthoridLeung, CH=7402612570en_US
dc.identifier.scopusauthoridBussom, S=16743813200en_US
dc.identifier.scopusauthoridCheng, YC=36041844200en_US

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