Antiproliferative effects of inhibitors of deoxyhypusine synthase. Inhibition of growth of Chinese hamster ovary cells by guanyl diamines.
Certain guanyl diamines are effective inhibitors of deoxyhypusine synthase (Jakus, J., Wolff, E. C., Park, M. H., and Folk, J. E. (1993) J. Biol. Chem. 268, 13151-13159), the first enzyme involved in the biosynthesis of the unusual amino acid hypusine (N epsilon-(4-amino-2-hydroxybutyl)lysine). Evidence that hypusine is implicated in cell growth prompted this study of the cellular effects of these inhibitors. In Chinese hamster ovary (CHO) cells, inhibition of hypusine biosynthesis followed by progressive arrest in cellular proliferation was observed with both N-mono- and N,N'-bisguanyl derivatives of 1,6-diaminohexane, 1,7-diaminoheptane, and 1,8-diaminooctane. Cells treated with these compounds showed no significant change in polyamine distribution, suggesting that the observed growth inhibition is not mediated through an interference with polyamine metabolism. N1-guanyl-1,7-diaminoheptane, the most potent inhibitor of deoxyhypusine synthase both in vitro and in cells, exhibited the highest antiproliferative activity toward CHO cells. No early cytotoxic effects were observed with this inhibitor, and its antiproliferative activity appeared to be reversible. Transport studies showed that N1-guanyl-1,7-diaminoheptane is actively taken up by the polyamine transport system. Mutant CHO cells defective in polyamine transport were found to be resistant to growth inhibition by this compound. The findings suggest that the antiproliferative effect of N1-guanyl-1,7-diaminoheptane is exerted intracellularly through inhibition of hypusine synthesis.
Enzyme Chemistry Section, NIDR, National Institutes of Health, Bethesda, Maryland 20892.
M H
MH
Park
E C
EC
Wolff
Y B
YB
Lee
J E
JE
Folk
D000818:Animals; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003959:Diamines / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007202:Indicators and Reagents; D007700:Kinetics; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors*; D011073:Polyamines / Q000378:metabolism*; D014176:Protein Biosynthesis; D011700:Putrescine / Q000378:metabolism; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D013329:Structure-Activity Relationship
D003959:Diamines; D007202:Indicators and Reagents; D011073:Polyamines; D013096:Spermine; C100028:hypusine; D006147:Guanine; D000587:Oxidoreductases Acting on CH-NH Group Donors; C063507:deoxyhypusine synthase; D008239:Lysine; D013095:Spermidine; D011700:Putrescine