Pourbagheri-Sigaroodi Atieh, Safaroghli-Azar Ava, Shanaki Mehrnoosh, Yousefi Amir-Mohammad, Anjam Najmedini Ali, Bashash Davood
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.
Iran J Pharm Res. 2020 Summer;19(3):144-155. doi: 10.22037/ijpr.2020.113170.14148.
An unbounded number of events exist beneath the intricacy of each particular hematologic malignancy, prompting the tumor cells into an unrestrained proliferation and invasion. Aberrant expression of cyclin-dependent kinases (CDKs) is one of these events which disrupts the regulation of cell cycle and subsequently, results in cancer progression. In this study, we surveyed the repressive impact of multi-CDK inhibitor AT7519 on a panel of leukemia-derived cell lines. Our data underlined that AT7519 abated the survival of all tested cells; however, in an overview, the response rate of leukemic cells to the inhibitor was varied irrespective of p53 status. Notably, the less sensitivity of leukemia cells to AT7519 was found to be mediated partly by the compensatory activation of c-Myc oncogene which was confirmed by the induction of a superior cytotoxicity upon its suppression in less sensitive cell. The blockage of cell cycle, as announced by induction of sub-G1 arrest as well as reduced S phase, resulted in a significant decrease in survival of acute promyelocytic leukemia (APL)-derived NB4 cells, as the most sensitive cell line, either as monotherapy or in combination with arsenic trioxide. Anti-leukemic effects of the inhibitor were further verified by apoptosis analysis, where we discovered that AT7519 induced apoptosis via alteration of pro- and anti-apoptotic genes in NB4. All in all, this study proposed that AT7519 is a rewarding agent opposed to APL; however, additional examinations should be performed to determine the advantages of this inhibitor in clinical setting.
在每一种特定血液系统恶性肿瘤的复杂性之下，存在着无数的事件，促使肿瘤细胞不受限制地增殖和侵袭。细胞周期蛋白依赖性激酶（CDKs）的异常表达就是其中之一，它扰乱了细胞周期的调控，进而导致癌症进展。在本研究中，我们调查了多 CDK 抑制剂 AT7519 对一组白血病衍生细胞系的抑制作用。我们的数据强调，AT7519 降低了所有测试细胞的存活率；然而，总体而言，白血病细胞对该抑制剂的反应率各不相同，与 p53 状态无关。值得注意的是，发现白血病细胞对 AT7519 的敏感性较低部分是由 c-Myc 癌基因的代偿性激活介导的，这在对较不敏感细胞中抑制该基因后诱导出更高的细胞毒性得到了证实。细胞周期的阻滞，如通过诱导亚 G1 期停滞以及 S 期减少所表明的，导致急性早幼粒细胞白血病（APL）衍生的 NB4 细胞（作为最敏感的细胞系）的存活率显著下降，无论是作为单一疗法还是与三氧化二砷联合使用。通过凋亡分析进一步验证了该抑制剂的抗白血病作用，我们发现 AT7519 通过改变 NB4 细胞中促凋亡和抗凋亡基因诱导凋亡。总而言之，本研究表明 AT7519 是一种对抗 APL 的有效药物；然而，应进行进一步的研究以确定该抑制剂在临床环境中的优势。
