Effects of uridine on the growth and differentiation of HL-60 leukemia cells.
HL-60 leukemia cells, induced to differentiate, activate a Na(+)-dependent nucleoside transport system, concomitant with a reduction in the nitrobenzylthioinosine (NBMPR)-sensitive facilitated transport of nucleosides. The consequence of these changes lead to the formation of intracellular pools of uridine. To examine the possible role of accumulated uridine in the commitment of HL-60 leukemia cells to undergo maturation, the effects of uridine on the growth and differentiation of HL-60 cells were monitored. Uridine at millimolar levels caused a concentration-dependent inhibition of cellular growth, resulting in the accumulation of cells in the G2/M phases of the cell cycle, phenomena that preceded the formation of differentiated cells. These effects of uridine were reduced by 10 microM NBMPR, an inhibitor of the facilitated transport of nucleosides. The effects of 24 mM uridine on growth and differentiation of HL-60 cells were also prevented by 5 mM inosine, and partially prevented by either 2 mM hypoxanthine or 20 microM adenosine. Pretreatment of HL-60 cells with 24 mM uridine for 6 days, followed by a 2 h exposure to TPA, resulted in the rapid attachment of cells to the tissue culture dish, and the extension of long processes. Although the concentrations of uridine required for the above effects are greater than those achieved during differentiation, these observations suggest that uridine may play a role in regulating the maturation process.
Sokoloski
J A
JA
Department of Pharmacology and Developmental Therapeutics Program, Yale University School of Medicine, New Haven, CT 06510.
Lee
C W
CW
Handschumacher
R E
RE
Nigam
A
A
Sartorelli
A C
AC
D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D009580:Nitroblue Tetrazolium; D010641:Phenotype; D012265:Ribonucleotides / Q000032:analysis; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014529:Uridine / Q000494:pharmacology*
D012265:Ribonucleotides; D009580:Nitroblue Tetrazolium; D014529:Uridine