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Apoptosis-inducing antitumor efficacy of hexokinase II inhibitor in hepatocellular carcinoma

Cited 75 time in Web of Science Cited 86 time in Scopus
Authors
Kim, Won; Yoon, Jung-Hwan; Jeong, Jae-Min; Cheon, Gi-Jeong; Lee, Tae-Sup; Yang, Jong-In; Park, Su-Cheol; Lee, Hyo-Suk
Issue Date
2007-09-19
Publisher
American Association for Cancer Research
Citation
Mol Cancer Ther. 2007 Sep;6(9):2554-62.
Keywords
AnimalsAnnexin A5/metabolismAnoxiaApoptosis/*drug effectsAzirinesCarcinoma, Hepatocellular/*drug therapy/enzymology/metabolismEnzyme Inhibitors/pharmacokinetics/*pharmacologyFlow CytometryHexokinase/*antagonists & inhibitors/metabolismHumansImmunoblottingImmunoprecipitationLiver Neoplasms, Experimental/*drug therapy/enzymology/metabolismMaleMiceMice, Inbred C3HMitochondria/drug effects/metabolismPhosphatidylcholinesPyruvate Dehydrogenase Complex/antagonists & inhibitorsPyruvates/pharmacokinetics/*pharmacologyTissue DistributionTumor Cells, Cultured
Abstract
Hypoxia stimulates hepatocellular carcinoma (HCC) cell growth via hexokinase (HK) II induction, and alternatively, HK II inhibition induces apoptosis by activating mitochondrial signaling. This study was to investigate whether the induction of HK II by hypoxia is associated with enhanced mitochondrial stability and to confirm the apoptosis-inducing efficacy of HK II inhibitor in an in vivo model of HCC. Mitochondrial stability was examined by treating isolated mitochondria with deoxycholate, a permeability-enhancing agent. Alteration of permeability transition pore complex composition was analyzed by immunoprecipitation and immunoblotting. An in vivo model of HCC was established in C3H mice i.d. implanted with MH134 cells. The antitumor efficacy of i.p. given 3-bromopyruvate (3-BrPA), a HK II inhibitor, was evaluated by measuring tumor volumes and quantifying apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining and (99m)Tc-hydrazinonicotinamide-Annexin V scans. Hypoxia enhanced mitochondrial stability, and this was inhibited by 3-BrPA treatment. In particular, HK II levels in permeability transition pore complex immunoprecipitates were reduced after 3-BrPA treatment. In mice treated with 3-BrPA, mean tumor volumes and tumor volume growth were found to be significantly reduced. Moreover, percentages of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were significantly increased in 3-BrPA-treated mice, and this apoptosis-inducing efficacy was reflected in vivo by (99m)Tc-hydrazinonicotinamide-Annexin V imaging. Our results show that hypoxia enhances mitochondrial stability via HK II induction and that HK II inhibitor treatment exhibits an in vivo antitumor effect by inducing apoptosis. Therefore, HK II inhibitors may be therapeutically useful for the treatment of advanced infiltrative hypovascular HCCs, which are growing in a hypoxic environment.
ISSN
1535-7163 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17876052

http://hdl.handle.net/10371/23066
DOI
https://doi.org/10.1158/1535-7163.MCT-07-0115
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College of Medicine/School of Medicine (의과대학/대학원)Program in Cancer Biology (협동과정-종양생물학전공)Journal Papers (저널논문_협동과정-종양생물학전공)
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