Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Student Research Committee, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Turk J Haematol. 2020 Aug 28;37(3):167-176. doi: 10.4274/tjh.galenos.2020.2019.0440. Epub 2020 Mar 12.
The association between PI3K overexpression and the acquisition of chemoresistance has attracted tremendous attention to this axis as an appealing target to revolutionize the conventional treatment strategies of human cancers. In the present study, we aimed to survey the inhibitory impact of the pan-PI3K inhibitor BKM120 on both cellular and molecular aspects of acute myeloid leukemia (AML)-derived KG-1 and U937 cells.
We designed various assays to survey the antitumor impacts and molecular mechanisms underlying the action of BKM120 for the treatment of AML, and we performed experiments to check the effect of BKM120 in combination with idarubicin.
We found that PI3K inhibition diminished cell viability and metabolic activity and exerted a concentration-dependent growth-suppressive effect on the cells. Moreover, we suggested that the ability of BKM120 to induce its antiproliferative properties was mediated through the induction of p21-mediated G2/M cell-cycle arrest. Investigating the effect of inhibitor on the molecular features revealed not only that BKM120 reduced the expression of NF-κB antiapoptotic targets, but also that NF-κB suppression using bortezomib profoundly enhanced the cytotoxicity of the inhibitor, highlighting that the antileukemic effects of BKM120 are mediated, at least partly, through the modulation of the NF-κB pathway. Interestingly, we found that the single agent of BKM120 was unable to significantly alter the expression level of ; however, the capability of BKM120 to reduce the survival rate of AML cells was potentiated upon inhibition using 10058-F4, suggestive of the plausible contribution of in leukemic cell response to the PI3K inhibitor.
Taken together, the results of this study reveal the efficacy of BKM120 as a therapeutic approach for AML; however, further investigations should be undertaken to determine the expediency of this inhibitor.
PI3K 过表达与获得化疗耐药之间的关联引起了人们对该轴的极大关注，将其作为革新人类癌症传统治疗策略的一个有吸引力的靶点。在本研究中，我们旨在调查泛 PI3K 抑制剂 BKM120 对急性髓系白血病（AML）衍生的 KG-1 和 U937 细胞的细胞和分子方面的抑制作用。
我们设计了各种测定方法来调查 BKM120 治疗 AML 的抗肿瘤作用和作用机制，并进行了实验以检查 BKM120 与伊达比星联合使用的效果。
我们发现，PI3K 抑制降低了细胞活力和代谢活性，并对细胞产生了浓度依赖性的生长抑制作用。此外，我们提出 BKM120 诱导其增殖抑制特性的能力是通过诱导 p21 介导的 G2/M 细胞周期阻滞介导的。研究抑制剂对分子特征的影响不仅表明 BKM120 降低了 NF-κB 抗凋亡靶标的表达，而且使用硼替佐米抑制 NF-κB 也显著增强了抑制剂的细胞毒性，这表明 BKM120 的抗白血病作用至少部分是通过调节 NF-κB 途径介导的。有趣的是，我们发现单一 BKM120 药物不能显著改变 的表达水平；然而，当使用 10058-F4 抑制 时，BKM120 降低 AML 细胞存活率的能力增强，提示 在白血病细胞对 PI3K 抑制剂的反应中可能发挥作用。
综上所述，本研究的结果揭示了 BKM120 作为 AML 治疗方法的疗效；然而，应进一步进行研究以确定该抑制剂的适宜性。
