AT9283 exhibits antiproliferative effect on tyrosine kinase inhibitor‑sensitive and ‑resistant chronic myeloid leukemia cells by inhibition of Aurora A and Aurora B

  • Authors:
    • Tomoya Takeda
    • Masanobu Tsubaki
    • Shuji Genno
    • Chisato Nemoto
    • Yasuka Onishi
    • Yuuta Yamamoto
    • Motohiro Imano
    • Takao Satou
    • Shozo Nishida
  • View Affiliations

  • Published online on: August 18, 2020     https://doi.org/10.3892/or.2020.7739
  • Pages: 2211-2218
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Abstract

Imatinib is the gold standard in the conventional treatment of chronic myeloid leukemia (CML). However, some patients become resistant to imatinib therapy. To overcome this resistance, second‑generation (dasatinib, nilotinib, and bosutinib) and third‑generation (ponatinib) tyrosine kinase inhibitors (TKIs) have been developed and have been shown to be effective against refractory CML. Although these TKIs provide many benefits for patients with CML, advanced patients show resistance even to these TKIs. Therefore, novel therapeutic strategies are urgently needed for the treatment of TKI‑resistant CML patients. AT9283 is a multi‑targeted kinase inhibitor with potent activity against Janus kinase (JAK), Aurora kinases, and Abl. In the present study, we showed that AT9283 significantly decreased the cell viability of both TKI‑sensitive and TKI‑resistant CML cells as determined by trypan blue exclusion assay. In addition, cell cycle analysis, Annexin V assay, and caspase‑3/7 activity assay revealed that AT9283 increased the cell population in the G2/M phase and induced apoptosis. We investigated the molecular mechanisms underlying the decrease in cell viability upon treatment with AT9283 by western blotting. Interestingly, our results showed that AT9283 inhibited the expression of Aurora A, Aurora B, and downstream Histone H3 phosphorylation. In contrast, we observed no changes in the levels of Bcr‑Abl, signal transducer and activator of transcription 3 (STAT3), extracellular signal‑regulated kinase (ERK), and Akt phosphorylation. In addition, we found that AMG900, a selective Aurora A and Aurora B inhibitor, increased the G2/M phase cell population and induced apoptosis via inhibition of Aurora A and Aurora B in both TKI‑sensitive and TKI‑resistant CML cells. Our studies show that Aurora A and Aurora B are promising therapeutic targets for TKI‑sensitive and TKI‑resistant CML, and AT9283 may have potential clinical applications for the treatment of TKI‑resistant CML patients.
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November-2020
Volume 44 Issue 5

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Takeda T, Tsubaki M, Genno S, Nemoto C, Onishi Y, Yamamoto Y, Imano M, Satou T and Nishida S: AT9283 exhibits antiproliferative effect on tyrosine kinase inhibitor‑sensitive and ‑resistant chronic myeloid leukemia cells by inhibition of Aurora A and Aurora B. Oncol Rep 44: 2211-2218, 2020
APA
Takeda, T., Tsubaki, M., Genno, S., Nemoto, C., Onishi, Y., Yamamoto, Y. ... Nishida, S. (2020). AT9283 exhibits antiproliferative effect on tyrosine kinase inhibitor‑sensitive and ‑resistant chronic myeloid leukemia cells by inhibition of Aurora A and Aurora B. Oncology Reports, 44, 2211-2218. https://doi.org/10.3892/or.2020.7739
MLA
Takeda, T., Tsubaki, M., Genno, S., Nemoto, C., Onishi, Y., Yamamoto, Y., Imano, M., Satou, T., Nishida, S."AT9283 exhibits antiproliferative effect on tyrosine kinase inhibitor‑sensitive and ‑resistant chronic myeloid leukemia cells by inhibition of Aurora A and Aurora B". Oncology Reports 44.5 (2020): 2211-2218.
Chicago
Takeda, T., Tsubaki, M., Genno, S., Nemoto, C., Onishi, Y., Yamamoto, Y., Imano, M., Satou, T., Nishida, S."AT9283 exhibits antiproliferative effect on tyrosine kinase inhibitor‑sensitive and ‑resistant chronic myeloid leukemia cells by inhibition of Aurora A and Aurora B". Oncology Reports 44, no. 5 (2020): 2211-2218. https://doi.org/10.3892/or.2020.7739