Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Int J Biochem Cell Biol. 2017 Apr;85:149-158. doi: 10.1016/j.biocel.2017.02.007. Epub 2017 Feb 22.
Genetic and laboratory experiments have brought remarkable advances in management of human malignancies, which not only revolutionized the understanding of the disease, but also led to development of novel and effective targeted therapies against specific deregulated pathways. This study aimed to investigate anti-cancer effects of Idelalisib, a potent PI3K-δ inhibitor, in a panel of hematological cell lines. The resulting data showed that Idelalisib decreased cell survival in all the tested cell lines; however, as compared to NB4, viability of other cell lines, irrespective of their molecular characteristics or even the compensatory activation of MEK/ERK pathway, was inhibited at higher concentrations. This study suggests for the first time that there is a significant correlation between relative response to Idelalisib and basal expression levels of anti-apoptotic genes, in particular survivin and MCL-1. Intriguingly, we found that Idelalisib-induced apoptosis in NB4, as the most sensitive cell line with the lowest expression level of the aforementioned genes, is executed probably via alteration in the transcriptional level of apoptosis-related genes coupled with p21-mediated caspase-3 activation. Moreover, the lower concentrations of Idelalisib combined with arsenic trioxide (ATO) produced synergistic anti-cancer effect in APL-derived NB4 cells. Overall, due to the pharmacologic safety of Idelalisib and its broad clinical effectiveness in chronic lymphoproliferative disorders, our study suggests that this inhibitor is a promising agent for the treatment of acute promyelocytic leukemia, either as single agent or in a combined-modality strategy.
遗传和实验室实验在人类恶性肿瘤的治疗方面带来了显著的进展，不仅彻底改变了人们对这种疾病的认识，而且还开发出了针对特定失调途径的新型有效靶向治疗方法。本研究旨在研究 Idelalisib（一种有效的 PI3K-δ 抑制剂）在一系列血液细胞系中的抗癌作用。结果数据表明，Idelalisib 降低了所有测试细胞系中的细胞存活率；然而，与 NB4 相比，其他细胞系的活力，无论其分子特征如何，甚至 MEK/ERK 途径的代偿性激活如何，在更高浓度下受到抑制。本研究首次表明，相对对 Idelalisib 的反应与抗凋亡基因（特别是 survivin 和 MCL-1）的基础表达水平之间存在显著相关性。有趣的是，我们发现，Idelalisib 在 NB4 中诱导的细胞凋亡（作为表达水平最低的最敏感细胞系）可能是通过改变与 p21 介导的 caspase-3 激活相关的凋亡相关基因的转录水平来执行的。此外，较低浓度的 Idelalisib 与三氧化二砷（ATO）联合使用在 APL 衍生的 NB4 细胞中产生协同抗癌作用。总体而言，由于 Idelalisib 的药理安全性及其在慢性淋巴细胞增生性疾病中的广泛临床有效性，我们的研究表明，该抑制剂是治疗急性早幼粒细胞白血病的有前途的药物，无论是单独使用还是联合使用。
