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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Hypoxia-inducible factor 1α inhibitor induces cell death via suppression of BCR-ABL1 and Met expression in BCR-ABL1 tyrosine kinase inhibitor sensitive and resistant chronic myeloid leukemia cells

  • Masanobu Tsubaki (Division of Pharmacotherapy, Kindai University Faculty of Pharmacy) ;
  • Tomoya Takeda (Division of Pharmacotherapy, Kindai University Faculty of Pharmacy) ;
  • Takuya Matsuda (Division of Pharmacotherapy, Kindai University Faculty of Pharmacy) ;
  • Akihiro Kimura (Division of Pharmacotherapy, Kindai University Faculty of Pharmacy) ;
  • Remi Tanaka (Division of Pharmacotherapy, Kindai University Faculty of Pharmacy) ;
  • Sakiko Nagayoshi (Division of Pharmacotherapy, Kindai University Faculty of Pharmacy) ;
  • Tadafumi Hoshida (Division of Pharmacotherapy, Kindai University Faculty of Pharmacy) ;
  • Kazufumi Tanabe (Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center) ;
  • Shozo Nishida (Division of Pharmacotherapy, Kindai University Faculty of Pharmacy)
  • Received : 2022.06.11
  • Accepted : 2022.09.16
  • Published : 2023.02.28
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Abstract

Chronic myeloid leukemia (CML) has a markedly improved prognosis with the use of breakpoint cluster region-abelson 1 (BCR-ABL1) tyrosine kinase inhibitors (BCR-ABL1 TKIs). However, approximately 40% of patients are resistant or intolerant to BCR-ABL1 TKIs. Hypoxia-inducible factor 1α (HIF-1α) is a hypoxia response factor that has been reported to be highly expressed in CML patients, making it a therapeutic target for BCR-ABL1 TKI-sensitive CML and BCR-ABL1 TKI-resistant CML. In this study, we examined whether HIF-1α inhibitors induce cell death in CML cells and BCR-ABL1 TKI-resistant CML cells. We found that echinomycin and PX-478 induced cell death in BCR-ABL1 TKIs sensitive and resistant CML cells at similar concentrations while the cell sensitivity was not affected with imatinib or dasatinib in BCR-ABL1 TKIs resistant CML cells. In addition, echinomycin and PX-478 inhibited the c-Jun N-terminal kinase (JNK), Akt, and extracellular-regulated protein kinase 1/2 (ERK1/2) activation via suppression of BCR-ABL1 and Met expression in BCR-ABL1 sensitive and resistant CML cells. Moreover, treatment with HIF-1α siRNA induced cell death by inhibiting BCR-ABL1 and Met expression and activation of JNK, Akt, and ERK1/2 in BCR-ABL1 TKIs sensitive and resistant CML cells. These results indicated that HIF-1α regulates BCR-ABL and Met expression and is involved in cell survival in CML cells, suggesting that HIF-1α inhibitors induce cell death in BCR-ABL1 TKIs sensitive and resistant CML cells and therefore HIF-1α inhibitors are potential candidates for CML treatment.

Keywords

Acknowledgement

This work was supported in part by a Grant-in-Aid for Scientific Research (C) (Grant numbers 20K07145 and 20K07168) from the Japan Society for the Promotion of Science (JSPS).

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