Zhao Jianyun, Xie Chengzhi, Edwards Holly, Wang Guan, Taub Jeffrey W, Ge Yubin
National Engineering Laboratory for AIDS Vaccine and Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, P. R. China.
Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
Oncotarget. 2017 Jan 24;8(4):6319-6329. doi: 10.18632/oncotarget.14062.
Resistance to chemotherapy and a high relapse rate highlight the importance of finding new therapeutic options for the treatment of acute myeloid leukemia (AML). Histone deacetylase (HDAC) inhibitors (HDACIs) are a promising class of drugs for the treatment of AML. HDACIs have limited single-agent clinical activities, but when combined with conventional or investigational drugs they have demonstrated favorable outcomes. Previous studies have shown that decreasing expression of important DNA damage repair proteins enhances standard chemotherapy drugs. In our recent studies, the pan-HDACI panobinostat has been shown to enhance conventional chemotherapy drugs cytarabine and daunorubicin in AML cells by decreasing the expression of BRCA1, CHK1, and RAD51. In this study, we utilized class- and isoform-specific HDACIs and shRNA knockdown of individual HDACs to determine which HDACs are responsible for decreased expression of BRCA1, CHK1, and RAD51 following pan-HDACI treatment in AML cells. We found that inhibition of both HDAC1 and HDAC2 was necessary to decrease the expression of BRCA1, CHK1, and RAD51, enhance cytarabine- or daunorubicin-induced DNA damage and apoptosis, and abrogate cytarabine- or daunorubicin-induced cell cycle checkpoint activation in AML cells. These findings may aid in the development of rationally designed drug combinations for the treatment of AML.
对化疗的耐药性和高复发率凸显了寻找急性髓系白血病（AML）新治疗方案的重要性。组蛋白去乙酰化酶（HDAC）抑制剂（HDACIs）是一类有前景的治疗AML的药物。HDACIs单药临床活性有限，但与传统或试验性药物联合使用时已显示出良好疗效。先前的研究表明，降低重要DNA损伤修复蛋白的表达可增强标准化疗药物的效果。在我们最近的研究中，泛HDAC抑制剂帕比司他已被证明可通过降低BRCA1、CHK1和RAD51的表达来增强AML细胞中传统化疗药物阿糖胞苷和柔红霉素的作用。在本研究中，我们使用了类别和亚型特异性HDACIs以及单个HDAC的短发夹RNA（shRNA）敲低技术，以确定在AML细胞中泛HDACIs治疗后，哪些HDACs导致BRCA1、CHK1和RAD51表达降低。我们发现，抑制HDAC1和HDAC2对于降低BRCA1、CHK1和RAD51的表达、增强阿糖胞苷或柔红霉素诱导的DNA损伤和凋亡以及消除阿糖胞苷或柔红霉素诱导的AML细胞周期检查点激活是必要的。这些发现可能有助于开发合理设计的治疗AML的联合用药方案。
