Grbovic Olivera, Jovic Viktor, Ruzdijic Sabera, Pejanovic Vjera, Rakic Ljubisav, Kanazir Selma
Laboratory of Molecular Neurobiology, Department of Neurobiology and Immunology, Institute for Biological Research, 29 Novembar 142, 11000 Belgrade, Yugoslavia.
Cancer Invest. 2002;20(7-8):972-82. doi: 10.1081/cnv-120005913.
8-Chloro-cyclic-adenosine-3',5'-monophosphate (8-Cl-cAMP), a site-selective synthetic cyclic adenosine 3',5'-monophosphate (cAMP) analog exhibits growth inhibition in a broad spectrum of human cancer lines. However, detailed studies on the effects exerted by cAMP analogs on cell-cycle kinetics have been lacking. We have examined and compared the effect of 8-Cl-cAMP on cell-cycle kinetics in two human glioma cell lines, U87MG (p53wt) and U251MG (p53mt). A flow cytometric analysis of cell-cycle distribution as well as apoptosis evaluation were performed by univariate DNA analysis after 24-72 hr of treatment with 10-50 M concentrations of 8-Cl-cAMP. Longer incubation with 8-Cl-cAMP induced dose related accumulation of cells in S phase and a subsequent decrease in the proportion of cells in G0/G1 phase of cell cycle in both cell lines. Time-dependent suppression of cyclin B1 was detected in both glioma cell lines and could be associated with observed G2 delay. However, 8-aCl-cAMP selectively induced apoptotic cell death only in U87MG, but not in U251MG cells. Induction of apoptosis was revealed both by flow cytometry and apoptotic cell morphology. These results provide an insight into the mechanism of 8-aCl-cAMP action, suggesting that the disturbance of cell-cycle kinetics and induction of apoptosis might contribute to its growth-inhibitory effect on cancer cells.
8-氯环磷酸腺苷（8-Cl-cAMP）是一种位点选择性合成的环磷酸腺苷（cAMP）类似物，在多种人类癌细胞系中均表现出生长抑制作用。然而，目前缺乏关于cAMP类似物对细胞周期动力学影响的详细研究。我们研究并比较了8-Cl-cAMP对两种人类胶质瘤细胞系U87MG（野生型p53）和U251MG（突变型p53）细胞周期动力学的影响。在用10 - 50 μM浓度的8-Cl-cAMP处理24 - 72小时后，通过单变量DNA分析进行细胞周期分布的流式细胞术分析以及凋亡评估。在两种细胞系中，与8-Cl-cAMP孵育更长时间会诱导S期细胞剂量相关的积累以及随后细胞周期G0/G1期细胞比例的下降。在两种胶质瘤细胞系中均检测到细胞周期蛋白B1的时间依赖性抑制，这可能与观察到的G2期延迟有关。然而，8-Cl-cAMP仅在U87MG细胞中选择性诱导凋亡性细胞死亡，而在U251MG细胞中未诱导。流式细胞术和凋亡细胞形态学均显示了凋亡的诱导。这些结果为8-Cl-cAMP的作用机制提供了深入了解，表明细胞周期动力学的紊乱和凋亡的诱导可能有助于其对癌细胞的生长抑制作用。
