Yao Chenjiao, Zhang Guojuan, Walker Alison, Zhao Kevin Y, Li Ying, Lyu Lei, Tang Yan, Ru Peng, Jones Dan, Zhao Weiqiang
Department of Hematology, The Third Xiang-ya Hospital of Central South University, Changsha, China.
The James Polaris Molecular Laboratory, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.
Leuk Res. 2017 Sep;60:129-134. doi: 10.1016/j.leukres.2017.08.003. Epub 2017 Aug 9.
We have previously shown that givinostat can induce potent apoptosis in the BCR-ABL1-positive, TP53-wild type B-cell acute lymphoblastic leukemia (B-ALL) cell line SUP-B15. We extend our studies here to two additional B-ALL cell lines, BCR-ABL1-negative CCRF-SB and p210 BCR-ABL1-positive NAML1. Givinostat induced significant cell growth inhibition in both cell lines, with an IC50 of 0.65±0.052μM and 0.25±0.028μM in CCRF-SB and NAML1, respectively. The key signal protein of the BCR-ABL1, Crk-L1, was significantly reduced by givinostat treatment in NAML1. As in SUP-B15, givinostat induced apoptosis in both cell lines but showed different levels of cleavage of the procaspase proteins Casp-3, Casp-7 and PARP. Levels of cell cycle-DNA repair regulator p21, CHK1 and FANCD2 levels were markedly affected by givinostat treatment. These data further enrich our understanding of the mechanisms of the antineoplastic effects of givinostat in B-ALL and provide a preclinical rationale for the inclusion of givinostat or similar agent in leukemia therapy.
我们之前已经表明，吉维司他能在BCR-ABL1阳性、TP53野生型的B细胞急性淋巴细胞白血病（B-ALL）细胞系SUP-B15中诱导强烈的细胞凋亡。我们在此将研究扩展至另外两个B-ALL细胞系，即BCR-ABL1阴性的CCRF-SB和p210 BCR-ABL1阳性的NAML1。吉维司他在这两个细胞系中均诱导了显著的细胞生长抑制，在CCRF-SB和NAML1中的IC50分别为0.65±0.052μM和0.25±0.028μM。在NAML1中，吉维司他处理显著降低了BCR-ABL1的关键信号蛋白Crk-L1。与在SUP-B15中一样，吉维司他在这两个细胞系中均诱导了细胞凋亡，但在procaspase蛋白Casp-3、Casp-7和PARP的切割水平上有所不同。细胞周期-DNA修复调节因子p21、CHK1和FANCD2的水平受到吉维司他处理的显著影响。这些数据进一步丰富了我们对吉维司他在B-ALL中抗肿瘤作用机制的理解，并为在白血病治疗中纳入吉维司他或类似药物提供了临床前依据。
