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.