Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes
Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes
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DOI：
10.1182/blood-2002-07-2339
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发表时间：
2003-05-01
期刊：
影响因子：
20.3
通讯作者：
Gil, J
中科院分区：
文献类型：
--
作者：
Campàs, C;López, JM;Gil, J
阿卡地新，5-氨基咪唑-4-甲酰胺（AICA）核苷，在所有测试样品（n = 70）中诱导B细胞慢性淋巴细胞白血病（B-CLL）细胞凋亡。B-CLL细胞的半数最大有效浓度（EC 50）为380 +/-60 μ M（n = 5）。半胱天冬酶抑制剂Z-VAD. favor完全阻断阿卡地辛诱导的细胞凋亡，其涉及半胱天冬酶-3、-8和-9的活化和细胞色素c的释放。用阿卡地新孵育B-CLL细胞诱导腺苷一磷酸活化蛋白激酶（AMPK）的磷酸化，表明其被阿卡地新活化。核苷转运抑制剂硝基苄硫代肌苷（NBTI）、腺苷激酶抑制剂5-碘杀结核菌素和腺苷完全抑制阿卡地辛诱导的细胞凋亡和AMPK磷酸化，表明阿卡地辛掺入细胞及其随后磷酸化为AICA核糖核苷酸（ZMP）是诱导细胞凋亡所必需的。蛋白激酶A和丝裂原活化蛋白激酶的抑制剂不能保护阿卡地辛诱导的B-CLL细胞凋亡。此外，阿卡地辛对p53水平或磷酸化没有影响，表明在细胞凋亡触发中存在p53非依赖性机制。正常B淋巴细胞对阿卡地辛诱导的细胞凋亡的敏感性与B-CLL细胞一样。然而，来自B-CLL患者的T细胞仅在高达4 mM的剂量下受到阿卡地辛的轻微影响。在用阿卡地辛处理的T细胞中未发生AMPK磷酸化。当用0.5 mM阿卡地新处理时，B-CLL细胞中ZMP的细胞内水平高于T细胞，表明ZMP积累对于激活AMPK和诱导细胞凋亡是必需的。这些结果表明了一种涉及AMPK控制B-CLL细胞凋亡的新途径，并提高了使用阿卡地辛治疗B-CLL的可能性。(C)2003年，美国血液学会。
Acadesine, 5-aminolmidazole-4-carboxamide (AICA) riboside, induced apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells in all samples tested (n = 70). the half-maximal effective concentration (EC50) for B-CLL cells was 380 +/- 60 muM (n = 5). The caspase inhibitor Z-VAD.fmk completely blocked acadesine-induced apoptosis, which involved the activation of caspase-3, -8, and -9 and cytochrome c release. Incubation of B-CLL cells with acadesine induced the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), indicating that it is activated by acadesine. Nitrobenzylthioinosine (NBTI), a nucleoside transport inhibitor, 5-iodotubercidin, an inhibitor of adenosine kinase, and adenosine completely inhibited acadesine-induced apoptosis and AMPK phosphorylation, demonstrating that incorporation of acadesine into the cell and its subsequent phosphorylation to AICA ribotide (ZMP) are necessary to induce apoptosis. Inhibitors of protein kinase A and mitogen-activated protein kinases did not protect from acadesine-induced apoptosis in B-CLL cells. Moreover, acadesine had no effect on p53 levels or phosphorylation, suggesting a p53-independent mechanism in apoptosis triggering. Normal B lymphocytes were as sensitive as B-CLL cells to acadesine-induced apoptosis. However, T cells from patients with B-CLL were only slightly affected by acadesine at doses up to 4 mM. AMPK phosphorylation did not occur in T cells treated with acadesine. Intracellular levels of ZMP were higher in B-CLL cells than in T cells when both were treated with 0.5 mM acadesine, suggesting that ZMP accumulation is necessary to activate AMPK and induce apoptosis. These results suggest a new pathway involving AMPK in the control of apoptosis in B-CLL cells and raise the possibility of using acadesine in B-CLL treatment. (C) 2003 by The American Society of Hematology.