新型芳基吲哚马来酰亚胺PDA-66在急性淋巴细胞白血病细胞中显示出显著的抗增殖作用。

The novel arylindolylmaleimide PDA-66 displays pronounced antiproliferative effects in acute lymphoblastic leukemia cells.

作者信息

Kretzschmar Christin, Roolf Catrin, Langhammer Tina-Susann, Sekora Anett, Pews-Davtyan Anahit, Beller Matthias, Frech Moritz J, Eisenlöffel Christian, Rolfs Arndt, Junghanss Christian

机构信息

Department of Hematology/Oncology/Palliative Medicine, Division of Medicine, University of Rostock, Ernst-Heydemann-Str, 6, Rostock 18057, Germany.

出版信息

BMC Cancer. 2014 Feb 6;14:71. doi: 10.1186/1471-2407-14-71.

BACKGROUND

Prognosis of adult patients suffering from acute lymphoblastic leukemia (ALL) is still unsatisfactory. Targeted therapy via inhibition of deregulated signaling pathways appears to be a promising therapeutic option for the treatment of ALL. Herein, we evaluated the influence of a novel arylindolylmaleimide (PDA-66), a potential GSK3β inhibitor, on several ALL cell lines.

METHODS

ALL cell lines (SEM, RS4;11, Jurkat and MOLT4) were exposed to different concentrations of PDA-66. Subsequently, proliferation, metabolic activity, apoptosis and necrosis, cell cycle distribution and protein expression of Wnt and PI3K/Akt signaling pathways were analyzed at different time points.

RESULTS

PDA-66 inhibited the proliferation of ALL cells significantly by reduction of metabolic activity. The 72 h IC50 values ranged between 0.41 to 1.28 μM PDA-66. Additionally, caspase activated induction of apoptosis could be detected in the analyzed cell lines. PDA-66 influenced the cell cycle distribution of ALL cell lines differently. While RS4;11 and MOLT4 cells were found to be arrested in G2 phase, SEM cells showed an increased cell cycle in G0/1 phase.

CONCLUSION

PDA-66 displays significant antileukemic activity in ALL cells and classifies as candidate for further evaluation as a potential drug in targeted therapy of ALL.

背景

成年急性淋巴细胞白血病（ALL）患者的预后仍不尽人意。通过抑制失调的信号通路进行靶向治疗似乎是治疗ALL的一种有前景的治疗选择。在此，我们评估了一种新型芳基吲哚马来酰亚胺（PDA - 66），一种潜在的糖原合成酶激酶3β（GSK3β）抑制剂，对几种ALL细胞系的影响。

方法

将ALL细胞系（SEM、RS4;11、Jurkat和MOLT4）暴露于不同浓度的PDA - 66。随后，在不同时间点分析细胞增殖、代谢活性、凋亡和坏死、细胞周期分布以及Wnt和PI3K/Akt信号通路的蛋白表达。

结果

PDA - 66通过降低代谢活性显著抑制ALL细胞的增殖。72小时半数抑制浓度（IC50）值在0.41至1.28μM PDA - 66之间。此外，在所分析的细胞系中可检测到半胱天冬酶激活诱导的凋亡。PDA - 66对ALL细胞系的细胞周期分布影响不同。虽然发现RS4;11和MOLT4细胞停滞在G2期，但SEM细胞在G0/1期的细胞周期增加。