The Impact of Hypoxic Treatment on the Expression of Phosphoglycerate Kinase and the Cytotoxicity of Troxacitabine and Gemcitabine
| العنوان: | The Impact of Hypoxic Treatment on the Expression of Phosphoglycerate Kinase and the Cytotoxicity of Troxacitabine and Gemcitabine |
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| المؤلفون: | Wing Lam, Scott Bussom, Yung-Chi Cheng, Chung-Hang Leung |
| المصدر: | Molecular Pharmacology. 72:536-544 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2007. |
| سنة النشر: | 2007 |
| مصطلحات موضوعية: | Antimetabolites, Antineoplastic, Carcinoma, Hepatocellular, Troxacitabine, Antineoplastic Agents, Biology, Deoxycytidine, Small hairpin RNA, Cytosine, Cell Line, Tumor, Rhabdomyosarcoma, DNA-(Apurinic or Apyrimidinic Site) Lyase, medicine, Humans, Clonogenic assay, Cytotoxicity, Pharmacology, Phosphoglycerate kinase, Gene knockdown, Carcinoma, Liver Neoplasms, Dioxolanes, Gemcitabine, Molecular biology, Cell Hypoxia, Pancreatic Neoplasms, Phosphoglycerate Kinase, Cell culture, Colonic Neoplasms, Molecular Medicine, Phosphorylation, medicine.drug |
| الوصف: | beta-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-1alpha (HIF-1alpha), 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 beta-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-1alpha 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. |
| تدمد: | 1521-0111 0026-895X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::825ebd074854426f8b752598232b26e8 https://doi.org/10.1124/mol.106.033472 |
| رقم الأكسشن: | edsair.doi.dedup.....825ebd074854426f8b752598232b26e8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210111 0026895X |
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