The morphological change of several
neuroblastoma cell lines induced by
griseolic acid, a novel and potent inhibitor of
cyclic nucleotide phosphodiesterase (PDE), was examined. In the cell lines tested, Neuro-2a (a murine
neuroblastoma cell line) showed dose-dependent (1 microM-1 mM) neurite extension.
Griseolic acid markedly increased the intracellular
cyclic AMP level of Neuro-2a cells, suppressed
DNA synthesis (82% at 1 mM), and induced multipolar (multiple-neurite-bearing)-type neuritogenesis. A similar type of neurite outgrowth was induced by 8-bromo-cyclic
AMP, which also elevated the intracellular
cyclic AMP concentration. In contrast, when Neuro-2a cells were treated with
retinoic acid, neurite formation was of the monopolar (single-neurite-bearing) type.
Papaverine and
theophylline, which have been frequently used as PDE inhibitors, failed to induce these morphological changes up to 1 mM, probably owing to the lesser potency of these compounds as compared with
griseolic acid on the inhibition of PDE.
Retinoic acid,
theophylline, and
papaverine were ineffective at elevating the intracellular
cyclic AMP level. These results suggest that multipolar-type cell shape change in Neuro-2a cells is correlated with the accumulation of intracellular
cyclic AMP and that
griseolic acid is a useful compound to induce
neuroblastoma cells into terminal differentiation.