PMID- 7622299
OWN - NLM
STAT- MEDLINE
DCOM- 19950829
LR  - 20190708
IS  - 0020-7136 (Print)
IS  - 0020-7136 (Linking)
VI  - 62
IP  - 2
DP  - 1995 Jul 17
TI  - Mitochondria-bound hexokinase as target for therapy of malignant gliomas.
PG  - 216-22
AB  - Hexokinase plays an important role in glucose-utilizing tissues like normal brain 
      and cancers. In these tissues, hexokinase (HK) is mainly bound to mitochondria 
      (mHK). Our objectives were to evaluate total HK (tHK) activity and mHK fraction 
      in gliomas and to determine whether mHK binding could be targeted for therapy. 
      Tumors were obtained from 26 patients and 13 were xenografted. HK, lactate and 
      ATP were measured in cytosol and mitochondria extracts. The tHK expressed in 
      mU/mg protein were 147 +/- 19 and 78 +/- 12, in fresh gliomas and xenografts, 
      respectively, and of 489 in the normal brain. The mHK fraction was 76% in normal 
      brain, 74 +/- 4% in fresh tumors and 53 +/- 6% in xenografts. Lactate/mHK ratios 
      were higher in gliomas than in normal brain. The ATP was 10, 52 +/- 31 and 19 +/- 
      8 nmol/mg protein in normal brain, xenografts and fresh gliomas respectively. 
      Loss of one copy of chromosome 10 which carries the HK1 gene, was evidenced in 11 
      of the 13 xenografted gliomas. The anti-tumor effect of lonidamine (LND), which 
      affects glycolysis in interfering with mHK activity, was tested in nude mice 
      bearing 4 gliomas. LND (125 mg/kg, given i.p., twice daily for 5 days) led to a 
      growth inhibition of TG-7-RO of 72%, with 2-fold growth retardation, and had no 
      effect for TG-8-OZ. Intermediate LND-sensitivities for TG-11-DU and TG-10-PY were 
      noted. The LND-sensitivity was correlated with the mHK activity (R2 = 0.73) and 
      mHK fraction (R2 = 0.88). HK binding to mitochondria is a key of glycolysis in 
      malignant gliomas, and targetting this binding with appropriate agents could be 
      an effective therapeutic approach.
FAU - Oudard, S
AU  - Oudard S
AD  - Laboratoire de Cytogenetique Moleculaire et Oncologie, UMR 147 CNRS, Institut 
      Curie, Paris, France.
FAU - Poirson, F
AU  - Poirson F
FAU - Miccoli, L
AU  - Miccoli L
FAU - Bourgeois, Y
AU  - Bourgeois Y
FAU - Vassault, A
AU  - Vassault A
FAU - Poisson, M
AU  - Poisson M
FAU - Magdelenat, H
AU  - Magdelenat H
FAU - Dutrillaux, B
AU  - Dutrillaux B
FAU - Poupon, M F
AU  - Poupon MF
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Indazoles)
RN  - 0 (Lactates)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.1.1 (Hexokinase)
RN  - U78804BIDR (lonidamine)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Adult
MH  - Aged
MH  - Animals
MH  - Female
MH  - Glioma/*enzymology
MH  - Hexokinase/*metabolism
MH  - Humans
MH  - Indazoles/*therapeutic use
MH  - Lactates/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Middle Aged
MH  - Mitochondria/*enzymology
MH  - Neoplasm Transplantation
EDAT- 1995/07/17 00:00
MHDA- 1995/07/17 00:01
CRDT- 1995/07/17 00:00
PHST- 1995/07/17 00:00 [pubmed]
PHST- 1995/07/17 00:01 [medline]
PHST- 1995/07/17 00:00 [entrez]
AID - 10.1002/ijc.2910620218 [doi]
PST - ppublish
SO  - Int J Cancer. 1995 Jul 17;62(2):216-22. doi: 10.1002/ijc.2910620218.