Mitsui K, Tsuji S, Yamazaki M, Nagai Y
Department of Biochemistry, Faculty of Medicine, University of Tokyo, Japan.
J Neurochem. 1991 Aug;57(2):556-61. doi: 10.1111/j.1471-4159.1991.tb03786.x.
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.
研究了新型强效环核苷酸磷酸二酯酶（PDE）抑制剂灰黄霉素酸诱导几种神经母细胞瘤细胞系的形态变化。在所测试的细胞系中，Neuro-2a（一种小鼠神经母细胞瘤细胞系）表现出剂量依赖性（1 microM - 1 mM）的神经突延伸。灰黄霉素酸显著提高了Neuro-2a细胞的细胞内环状AMP水平，抑制DNA合成（1 mM时为82%），并诱导多极（带有多个神经突）型神经突形成。8-溴环AMP也诱导了类似类型的神经突生长，其也提高了细胞内环状AMP浓度。相比之下，当Neuro-2a细胞用视黄酸处理时，神经突形成是单极（带有单个神经突）型。经常用作PDE抑制剂的罂粟碱和茶碱在高达1 mM时未能诱导这些形态变化，这可能是由于与灰黄霉素酸相比，这些化合物对PDE的抑制效力较低。视黄酸、茶碱和罂粟碱在提高细胞内环状AMP水平方面无效。这些结果表明，Neuro-2a细胞中的多极型细胞形状变化与细胞内环状AMP的积累相关，并且灰黄霉素酸是一种将神经母细胞瘤细胞诱导为终末分化的有用化合物。
