Inhibition of Pim-2 kinase by LT-171-861 promotes DNA damage and exhibits enhanced lethal effects with PARP inhibitor in multiple myeloma
Inhibition of Pim-2 kinase by LT-171-861 promotes DNA damage and exhibits enhanced lethal effects with PARP inhibitor in multiple myeloma
复制标题
LT-171-861 抑制 Pim-2 激酶可促进 DNA 损伤，并在多发性骨髓瘤中表现出增强的 PARP 抑制剂致死作用
DOI：
10.1016/j.bcp.2021.114648
复制
发表时间：
2021
影响因子：
5.8
通讯作者：
Na Lu
中科院分区：
文献类型：
--
作者：
Cen Zhao;Dawei Yang;Yuchen Ye;Zhenzhong Chen;Tifan Sun;Jiawei Zhao;Kai Zhao;Na Lu
多发性骨髓瘤（MM）是一种以基因组不稳定和遗传异常为标志的浆细胞恶性肿瘤。因此，DNA损伤在MM细胞中是普遍的，这表明不规则的DNA损伤反应（DDR）途径。在这项研究中，我们证明了LT-171-861，一种多激酶抑制剂，可以抑制MM细胞的增殖并诱导凋亡。LT-171-861促进DDR通路，并通过阻碍双链断裂中的同源重组过程触发DNA损伤，而不是直接升高MM细胞中的ROS水平。机制研究表明，Pim 2抑制负责LT-171-861诱导的DNA损伤和细胞凋亡。LT-171-861主要抑制Pim 2激酶活性并减少其磷酸化底物（如4 EBP 1和BAD）的表达。此外，奥拉帕尼（一种PARP抑制剂）可增强LT-171-861在MM异种移植裸鼠中抑制肿瘤生长的抗肿瘤作用。综上所述，我们的结果表明LT-171-861显示出对MM的有希望的治疗潜力，并且与PARP抑制剂一起具有额外的致死作用。
Multiple myeloma (MM) is a malignancy of antibody-producing plasma cells with genomic instability and genetic abnormality as its two hallmarks. Therefore, DNA damage is pervasive in MM cells, which indicates irregular DNA damage response (DDR) pathway. In this study, we demonstrated that LT-171-861, a multiple kinase inhibitor, could inhibit proliferation and induce apoptosis in MM cells. LT-171-861 promoted DDR pathway and triggered DNA damage through impeding the process of homologous recombination in double strand breaks, rather than directly elevating ROS level in MM cells. Mechanism research revealed that Pim2 inhibition was responsible for LT-171-861-indcued DNA damage and cell apoptosis. LT-171-861 mainly suppressed Pim2 kinase activity and reduced the expression of its phosphorylated substrates, such as 4EBP1 and BAD. Moreover, Olaparib, a PARP inhibitor, could enhance the antitumor effect of LT-171-861 in suppressing tumor growth in MM xenografted nude mice. Taken together, our results demonstrated that LT-171-861 showed a promising therapeutic potential for MM and had an additional lethal effect with PARP inhibitors.