Jilin Provincial Key Laboratory of BioMacromolecules of Chinese Medicine, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, Jilin, China.
Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin, China.
Biochem Pharmacol. 2019 Jun;164:273-282. doi: 10.1016/j.bcp.2019.04.022. Epub 2019 Apr 20.
Resistance to standard induction therapy and relapse remain the primary challenges for improving therapeutic effects in acute myeloid leukemia (AML); thus, novel therapeutic strategies are urgently required. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of different types of DNA damage, which is crucial for the maintenance of genomic integrity. The ATR-selective inhibitor VE-822 has proper solubility, potency, and pharmacokinetic properties. In this study, we investigated the anti-leukemic effects of VE-822 alone or combined with Wee1-selective inhibitor AZD1775 in AML cells. Our results showed that VE-822 inhibited AML cell proliferation and induced apoptosis in a dose-dependent manner. AZD1775 significantly promoted VE-822-induced inhibition of AML cell proliferation and led to a decreased number of cells in the G2/M phase. VE-822 and AZD1775 decreased the protein levels of ribonucleotide reductase M1 (RRM1) and M2 (RRM2) subunits, key enzymes in the synthesis of deoxyribonucleoside triphosphate, which increased DNA replication stress. VE-822 combined with AZD1775 synergistically induced AML cell apoptosis and led to replication stress and DNA damage in AML cell lines. Our study demonstrated that AZD1775 synergistically promotes VE-822-induced anti-leukemic activity in AML cell lines and provides support for clinical research on VE-822 in combination with AZD1775 for the treatment of AML patients.
耐药性和复发仍是急性髓细胞白血病（AML）治疗效果改善的主要挑战；因此，迫切需要新的治疗策略。共济失调毛细血管扩张症和 Rad3 相关蛋白（ATR）是多种类型 DNA 损伤的关键调节剂，对维持基因组完整性至关重要。ATR 选择性抑制剂 VE-822 具有适当的溶解性、效力和药代动力学特性。在这项研究中，我们研究了 VE-822 单独或与 Wee1 选择性抑制剂 AZD1775 联合应用于 AML 细胞的抗白血病作用。结果表明，VE-822 呈剂量依赖性抑制 AML 细胞增殖并诱导细胞凋亡。AZD1775 显著促进 VE-822 诱导的 AML 细胞增殖抑制，并导致 G2/M 期细胞数量减少。VE-822 和 AZD1775 降低了核糖核苷酸还原酶 M1（RRM1）和 M2（RRM2）亚基的蛋白水平，这是脱氧核苷三磷酸合成的关键酶，增加了 DNA 复制应激。VE-822 联合 AZD1775 协同诱导 AML 细胞凋亡，并导致 AML 细胞系中复制应激和 DNA 损伤。本研究表明，AZD1775 协同促进 AML 细胞系中 VE-822 诱导的抗白血病活性，为 VE-822 联合 AZD1775 治疗 AML 患者的临床研究提供了支持。
