The cytostatic- and differentiation-inducing effects of cyclopentenyl cytosine on neuroblastoma cell lines

Abstract

This paper describes the effects of cyclopentenyl cytosine (CPEC) on the proliferation and cell-cycle distribution of the SK-N-BE(2)c and SK-N-SH neuroblastoma cell lines, as well as their ability to recover from treatment with CPEC. The ic 50 value of SK-N-BE(2)c for CPEC, determined after 48 hr was 80 nM. SK-N-BE(2)c cells showed a time- and concentration-dependent accumulation in the S-phase of the cell cycle after 2 and 3 days of incubation with 50–250 nM CPEC, followed by a G 0/G 1-phase arrest after 4 days. After incubation with 50 nM CPEC for 2 days, SK-N-BE(2)c cells fully recovered and resumed logarithmic proliferation. In contrast, a complete and persistent growth arrest occurred when SK-N-BE(2)c cells were incubated for 2 days with 100 or 250 nM CPEC. The ic 50 value of SK-N-SH, determined after 48 hr, for CPEC was ≥1 μM. SK-N-SH cells incubated with 250 nM or 1 μM CPEC showed a time-dependent accumulation in the S-phase of the cell cycle, followed by an accumulation in the G 0/G 1-phase, which reached a maximum of 84.1% after 7 days of incubation with 1 μM CPEC. SK-N-SH cells did not resume proliferation after removal of the drug. In addition, CPEC strongly induced differentiation in SK-N-SH cells. After 48 hr incubation with 250 nM CPEC, 90% of the cell population was differentiated. Both neuronal type and Schwannian type cells were observed. We conclude that at very low concentrations, CPEC has profound cytostatic- and differentiation-inducing effects on the neuroblastoma cells studied.