High Km glucose-phosphorylating (glucokinase) activities in a range of tumor cell lines and inhibition of rates of tumor growth by the specific enzyme inhibitor mannoheptulose.
Differences in modes of control of glycolysis in tumor cells, compared with normal cells, have suggested that phosphofructokinase may not catalyse the rate-controlling step. Instead, hexokinase activity may assume a more important regulatory role. Hexokinase activities are consistently lower than those of phosphofructokinase in tumor cells, and the former enzyme may be saturated with its substrate (M. Board et al., Biochem. J. 265: 503-509, 1990). The present work has focused on the glucose-phosphorylation step in tumor cell glycolysis. A range of eight human tumor cell-lines, one human tumor tissue, and four rat tumor cell lines were found to have an additional glucose-phosphorylating activity, with properties similar to hepatic glucokinase. Maximal activities range from 1.1-20 nmol/min/mg cell protein, and the activity is consistently absent from any untransformed cell line or tissue tested, except rat liver tissue (18 nmol/min/mg cell protein). Tumor cell glucokinase activity has been characterized by its high Km for glucose (8-11.8 mM); inhibition by the specific glucokinase inhibitor, mannoheptulose (I50, 12.5 mM); and lack of inhibition by 10 mM glucose-6-phosphate. Mannoheptulose also causes inhibition of glucose uptake by tumor cells (25-75% at 30 mM mannoheptulose) and inhibition of rates of growth of cultured tumor cell lines (I50, 21.4 mM). Rates of growth of human tumors in experimental animals are dramatically reduced (by 65-79%) by a dose of 1.7 mg/g mannoheptulose daily for 5 days. The potential of the naturally occurring sugar, mannoheptulose (which is purified from avocados and is assumed to be of low toxicity), as a cancer treatment is discussed.
Board
M
M
Department of Biochemistry, University of Oxford, United Kingdom.
Colquhoun
A
A
Newsholme
E A
EA
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D005260:Female; D005941:Glucokinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006593:Hexokinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008356:Mannoheptulose / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009206:Myocardium / Q000201:enzymology; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D013997:Time Factors; D014407:Tumor Cells, Cultured
D007527:Isoenzymes; D008356:Mannoheptulose; D017853:Phosphotransferases (Alcohol Group Acceptor); D006593:Hexokinase; D005941:Glucokinase; C018716:N-acetylglucosamine kinase; D005947:Glucose