A novel adenosine analog, thio-Cl-IB-MECA, induces G0/G1 cell cycle arrest and apoptosis in human promyelocytic leukemia HL-60 cells
A novel adenosine analog, thio-Cl-IB-MECA, induces G0/G1 cell cycle arrest and apoptosis in human promyelocytic leukemia HL-60 cells
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DOI：
10.1016/j.bcp.2005.06.017
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发表时间：
2005-09-15
影响因子：
5.8
通讯作者：
Lee, SK
中科院分区：
文献类型：
--
作者：
Lee, EJ;Min, HY;Lee, SK
人A（3）腺苷受体（A（3）AR）激动剂已被证明在多种生理和病理过程中发挥重要作用，包括人类癌细胞的生长抑制。在这方面，我们最近发现一种新的腺苷类似物，2-氯-N-6（3-碘苄基）-4 '-硫代腺苷-5'-N-甲基脲酰胺（硫代-Cl-IB-MECA）是一种有效的人A3 AR激动剂，并且比已知的激动剂Cl-IB-MECA好上级[Jeong LS，Jin DZ，Kim HO，Shin DH，Moon HR，Gunaga R等，J Med Chem 2003;46：3775]。本文报道一种新型A3 AR激动剂thio-Cl-IB-MECA通过阻滞细胞周期和诱导细胞凋亡抑制人早幼粒白血病HL-60细胞的生长。Thio-Cl-IB-MECA在早期和较低浓度（高达25 μ M）下诱导G（0）/G（1）I的细胞周期停滞。在较高浓度（50 μ M）下，通过观察到细胞周期分布的亚Go期增加、DNA断裂和聚（ADP-核糖）聚合酶（PARP）裂解来证明凋亡性细胞死亡。此外，thio-Cl-MECA下调细胞周期检查点蛋白cyclin DI和c-myc的表达与阻滞细胞周期由G1期向S期的转变密切相关。进一步的研究表明，thio-Cl-IB-MECA的生长抑制活性也与Wnt信号通路的调节有关。thio-Cl-IB-MECA（10 nM）以时间依赖性方式下调P-连环蛋白、磷酸化形式的GSK-β和Akt的水平，为thio-Cl-IB-MECA抑制HL-60细胞生长的作用中Wnt信号通路的参与提供了一个合理的机制证据。这些结果表明，新型A3 AR激动剂thio-Cl-IB-NIECA能够下调HL-60白血病细胞Wnt信号，抑制细胞增殖并诱导细胞凋亡，从而为该化合物在白血病治疗中的潜在治疗价值提供了可能。(c)2005年爱思唯尔公司All rights reserved.
Human A(3) adenosine receptor (A(3)AR) agonists have been shown to play important roles in several physiological and pathological processes, including growth inhibition of human cancer cells. On this line, we recently found that a novel adenosine analog, 2-chloro-N-6(3-iodobenzyl)-4'-thioadenosine-5'-N-methyluronamide (thio-Cl-IB-MECA) was a potent human A3AR agonist, and is superior to a known agonist Cl-IB-MECA [Jeong LS, Jin DZ, Kim HO, Shin DH, Moon HR, Gunaga R et al. J Med Chem 2003;46:3775]. Here, we report that a novel A3AR agonist, thio-Cl-IB-MECA inhibited the growth of human promyelocytic leukemia HL-60 cells by arresting cell cycle and induction of apoptosis. Thio-Cl-IB-MECA induced the cell cycle arrest of G(0)/G(1) I in the early time and at lower concentration (up to 25 mu M). At higher concentration (50 mu M), the apoptotic cell deaths were manifested by observation of the increase of sub-Go phase of cell cycle distribution, DNA fragmentation and poly(ADP-ribose) polymerase (PARP) cleavage. In addition, the down-regulation of checkpoint protein cyclin D I and c-myc by thio-Cl-MECA was well correlated with the arrest of cell cycle transition of G, to S phase. Further study revealed that the growth inhibitory activity of thio-Cl-IB-MECA is also related with the modulation of Wnt signaling pathway. The levels of P-catenin, phosphorylated forms of GSK-beta and Akt were down-regulated by the treatment of thio-Cl-IB-MECA (10 nM) in a time-dependent manner, providing one of plausible mechanistic evidence for the involvement of the Wnt signaling pathway in the HL-60 cell growth inhibitory effects by thio-Cl-IB-MECA. These results suggest that a novel A3AR agonist, thio-Cl-IB-NIECA can down-regulate Wnt signaling, inhibit proliferation and induce apoptosis in HL-60 leukemia cells, and thus provide the possibility of this compound in the potential therapeutic value of the treatment of leukemia. (c) 2005 Elsevier Inc. All rights reserved.