PMID- 17876052
OWN - NLM
STAT- MEDLINE
DCOM- 20071127
LR  - 20200930
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 6
IP  - 9
DP  - 2007 Sep
TI  - Apoptosis-inducing antitumor efficacy of hexokinase II inhibitor in 
      hepatocellular carcinoma.
PG  - 2554-62
AB  - 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.
FAU - Kim, Won
AU  - Kim W
AD  - Department of Internal Medicine and Liver Research Institute, Seoul National 
      University College of Medicine, Seoul, Korea.
FAU - Yoon, Jung-Hwan
AU  - Yoon JH
FAU - Jeong, Jae-Min
AU  - Jeong JM
FAU - Cheon, Gi-Jeong
AU  - Cheon GJ
FAU - Lee, Tae-Sup
AU  - Lee TS
FAU - Yang, Jong-In
AU  - Yang JI
FAU - Park, Su-Cheol
AU  - Park SC
FAU - Lee, Hyo-Suk
AU  - Lee HS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Annexin A5)
RN  - 0 (Azirines)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Phosphatidylcholines)
RN  - 0 (Pyruvate Dehydrogenase Complex)
RN  - 0 (Pyruvates)
RN  - 63JMV04GRK (bromopyruvate)
RN  - 86013-84-5 
      (1-palmitoyl-2-(10-(4-((trifluoromethyl)diazirinyl)phenyl)-8-oxadecanoyl)-sn-glycero-3-phosphocholine)
RN  - EC 2.7.1.1 (Hexokinase)
SB  - IM
MH  - Animals
MH  - Annexin A5/metabolism
MH  - Apoptosis/*drug effects
MH  - Azirines
MH  - Carcinoma, Hepatocellular/*drug therapy/enzymology/metabolism
MH  - Enzyme Inhibitors/pharmacokinetics/*pharmacology
MH  - Flow Cytometry
MH  - Hexokinase/*antagonists & inhibitors/metabolism
MH  - Humans
MH  - Hypoxia
MH  - Immunoblotting
MH  - Immunoprecipitation
MH  - Liver Neoplasms, Experimental/*drug therapy/enzymology/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Mitochondria/drug effects/metabolism
MH  - Phosphatidylcholines
MH  - Pyruvate Dehydrogenase Complex/antagonists & inhibitors
MH  - Pyruvates/pharmacokinetics/*pharmacology
MH  - Tissue Distribution
MH  - Tumor Cells, Cultured
EDAT- 2007/09/19 09:00
MHDA- 2007/12/06 09:00
CRDT- 2007/09/19 09:00
PHST- 2007/09/19 09:00 [pubmed]
PHST- 2007/12/06 09:00 [medline]
PHST- 2007/09/19 09:00 [entrez]
AID - 6/9/2554 [pii]
AID - 10.1158/1535-7163.MCT-07-0115 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2007 Sep;6(9):2554-62. doi: 10.1158/1535-7163.MCT-07-0115.