2. Academic Validation
  3. 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

  • Biochem Pharmacol. 2021 Aug;190:114648. doi: 10.1016/j.bcp.2021.114648.
Cen Zhao 1,  Dawei Yang 1,  Yuchen Ye 1,  Zhenzhong Chen 1,  Tifan Sun 1,  Jiawei Zhao 1,  Kai Zhao 2,  Na Lu 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
  • 2 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China. Electronic address: zhaokai@cpu.edu.com.
  • 3 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China. Electronic address: nalu@cpu.edu.cn.
PMID: 34111425 DOI: 10.1016/j.bcp.2021.114648
Abstract

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.

Keywords

Apoptosis; DNA damage response; Multiple myeloma; Pim2.

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