4.7 Article

Pseudolaric acid B induces mitotic arrest and apoptosis in both imatinib-sensitive and -resistant chronic myeloid leukaemia cells

Journal

EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 876, Issue -, Pages -

Publisher

ELSEVIER
DOI: 10.1016/j.ejphar.2020.173064

Keywords

Chronic myeloid leukaemia cells; PAB; BCR-ABL; Apoptosis; Cell cycle; Drug resistance

Funding

  1. NSFC [81670154/H0812, 81470355/H1616, 81100378/H0812]
  2. Foundation of Guangzhou Science and Technology Innovation Committee [201707010352, 1201410214, 2014A030313492, 201528042]
  3. Bureau of Education of Guangzhou Municipality
  4. GD-NSF
  5. Guangdong Special Support Scheme
  6. National Natural Science Foundation of China [81773213]
  7. National Funds for Developing Local Colleges and Universities [B16056001]
  8. Natural Science Foundation Research Team of Guangdong Province [2018B030312001]
  9. Science and Technology Program of Guangzhou [201604020001]
  10. Project of Department of Education of Guangdong Province [2016KTSCX119]
  11. Research Team of Department of Education of Guangdong Province [2017KCXTD027]

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The selective BCR-ABL tyrosine kinase inhibitor imatinib is one of the first-line therapies in the management of chronic myeloid leukaemia (CML). However, acquired resistance to this inhibitor, which is especially conferred by the T315I point mutation in BCR-ABL, impedes the efficacy of imatinib therapy. Therefore, the discovery and development of novel agents to overcome imatinib resistance is urgently needed. Pseudolaric acid B (PAB), a small molecule isolated from the traditional Chinese medicine Cortex pseudolaricis, has been reported to be a potential candidate for immune disorders and cancer treatment. However, its effects on CML and the involved molecular mechanism have not been reported. In the current study, by performing both in vitro and in vivo experiments in CML cells, we showed that PAB blocked the cell cycle at G(2)/M phase and subsequently activated the caspase pathway, cleaved the BCR-ABL protein and inhibited the BCR-ABL downstream pathways, ultimately leading to cell proliferation inhibition, cytotoxicity and apoptosis. These events were observed in both imatinib-sensitive and imatinib-insensitive CML cell lines. Moreover, PAB decreased the viability of primary blood mononuclear cells from CML patients and induced apoptosis in these cells. Our findings suggest that PAB could be used as a novel agent to sensitize imatinib-resistant CML.

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