Apoptosis induced by 2-chloro-adenosine and 2-chloro-2′-deoxy-adenosine in a human astrocytoma cell line:: Differential mechanisms and possible clinical relevance
Apoptosis induced by 2-chloro-adenosine and 2-chloro-2′-deoxy-adenosine in a human astrocytoma cell line:: Differential mechanisms and possible clinical relevance
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DOI：
10.1002/(sici)1097-4547(20000501)60:3
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发表时间：
2000-05-01
影响因子：
4.2
通讯作者：
Abbracchio, MP
中科院分区：
文献类型：
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作者：
Ceruti, S;Franceschi, C;Abbracchio, MP
我们先前已经证明了2-氯腺苷（2-CA）可以诱导大鼠星形胶质细胞凋亡（Abbracchio等，[1995] Biochem. Biophys，Res. Commun，213，908-915）。在本研究中，我们首次表征了对人星形细胞瘤细胞系的诱导作用2-CA及其相关类似物2-氯-2 '-脱氧腺苷（ADF细胞）（2-CdA，在慢性淋巴恶性肿瘤中用作抗癌剂）。这些细胞暴露于腺苷类似物导致时间和浓度依赖性细胞凋亡。用已知干扰腺苷受体、膜转运蛋白和胞内核苷激酶的药物进行的实验表明：（i）腺苷类似物诱导的细胞死亡不依赖于胞外腺苷受体，而是直接依赖于胞内作用，然而，只有在2-CA的情况下，才是由特异的硝基苄基硫代肌苷敏感的转运蛋白介导进入细胞;（ii）对于两种腺苷类似物，诱导细胞凋亡需要特异性细胞内核苷激酶的磷酸化/活化，即，腺苷激酶用于2-CA，脱氧胞苷激酶用于2-CdA。此外，只有在2-CdA的情况下，诱导细胞凋亡之前，在细胞周期的G2/M期的细胞块。最后，在杀死约80-90%星形细胞瘤细胞的任一类似物的浓度下，观察到对原代皮层神经元的活力的显著较低的影响。总之，两种腺苷类似物都可以触发人星形细胞瘤细胞的凋亡，尽管机制不同。这种效应加上神经元细胞的相对保留，可能对神经胶质源性肿瘤的治疗具有潜在的临床意义。(C)2000 Wiley-Liss，Inc.
We have previously demonstrated that il-chloro-adenosine (2-CA) can induce apoptosis of rat astroglial cells (Abbracchio et al, [1995] Biochem. Biophys, Res. Commun, 213, 908-915), In the present study, we have characterized, for the first time, the effects induced on a human astrocytoma cell line (ADF cells) by both 2-CA and its related analog 2-chloro-2'-deoxy-adenosine (2-CdA, that is employed as anti-cancer agent in chronic lymphoid malignancies). Exposure of these cells to either adenosine analog resulted in time- and concentration-dependent apoptosis. Experiments with pharmacological agents known to interfere with adenosine receptors, its membrane transporter, and intracellular nucleoside kinases showed that: (i) cell death induced by either adenosine analog did not depend on extracellular adenosine receptors, but on a direct intracellular action; however, only in the case of 2-CA, was entry into cells mediated by the specific nitrobenzyl-tioinosine-sensitive transporter; (ii) for both adenosine analogs, induction of apoptosis required the phosphorylation/activation by specific intracellular nucleoside kinases, i.e., adenosine kinase for 2-CA, and deoxycytidine kinase for 2-CdA. In addition, only in the case of 2-CdA, was induction of apoptosis preceded by a block of cells at the G2/M phase of the cell cycle. Finally, at concentrations of either analog that killed about 80-90% of astrocytoma cells, a significantly lower effect on the viability of primary cortical neurons was observed. In conclusion, both adenosine analogs can trigger apoptosis of human astrocytoma cells, albeit with different mechanisms. This effect together with the relative sparing of neuronal cells, may have potential clinical implications for the therapy of tumors of glial origin. (C) 2000 Wiley-Liss, Inc.