Differential effects of cell cycle inhibitors on primary astrocytes and glioma cells

Astrocytes remain in a state of quiescence in the mammalian central nervous system under normal circumstances, but enter the cell cycle during many pathological conditions. The sterol synthetic pathway is believed to play a role in regulating cell cycling. In the present study, we examined the effects upon astrocytic cell cultures of two cell cycle phase-specific inhibitors, hydroxyurea and the HMG CoA reductase inhibitor mevinolin. Primary astrocytes were obtained from neonatal rats. These cell cultures, as well as C6 glioma cells, were grown in DMEM + 10% bovine calf serum (BCS). After synclironization in DMEM f 0.1% BCS for 48 hours, they were incubated for different periods of time in DMEM + 10% BCS in the presence of graded concentrations of hydroxyurea and mevinolin. 'H-thymidine incorporation and protein content in cultures were measured. Kinetic study of cell proliferation revealed that C6 glioma cells entered S phase 3-4 h earlier than primary astrocytes after synchronization. Hydroxyurea caused a significant concentration-dependent inhibition of cell proliferation in primary astrocytes, which was not observed in C6 glioma cells. However, mevinolin inhibited cell proliferation in both cell cultures. In addition, hydroxyurea and mevinolin appeared synergistic in their inhibitory effects upon primary astrocytes, but not C6 glioma cells. Thus, not only do these results indicate the presence of different cell cycle regulatory mechanisms in the two types of cells, they also suggest possible interventions for selective targeting of neoplastic astroglia.