Mitochondria-bound hexokinase as target for therapy of malignant gliomas.
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.
Oudard
S
S
Laboratoire de Cytogénétique Moléculaire et Oncologie, UMR 147 CNRS, Institut Curie, Paris, France.
Poirson
F
F
Miccoli
L
L
Bourgeois
Y
Y
Vassault
A
A
Poisson
M
M
Magdelénat
H
H
Dutrillaux
B
B
Poupon
M F
MF
D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D005910:Glioma / Q000201:enzymology*; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D007773:Lactates / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology*; D009368:Neoplasm Transplantation
D007191:Indazoles; D007773:Lactates; D000255:Adenosine Triphosphate; D006593:Hexokinase; C016371:lonidamine