HSP90 inhibitors promote cell death by degrading Met and BCR::ABL1 in both imatinib-resistant and -sensitive chronic myeloid leukemia cells
Abstract Background Chronic myeloid leukemia is associated with a more favorable prognosis following treatment with BCR::ABL1 tyrosine kinase inhibitors (TKIs). Nonetheless, about 40% of affected individuals with CML display resistance or intolerance towards BCR::ABL1 TKIs. Heat shock protein 90 (HS...
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SpringerOpen
2025-01-01
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| Series: | Future Journal of Pharmaceutical Sciences |
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| Online Access: | https://doi.org/10.1186/s43094-025-00767-w |
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| author | Masanobu Tsubaki Taira Matsuo Rie Komori Noriaki Nagai Tetsushi Yamamoto Shozo Nishida |
| author_facet | Masanobu Tsubaki Taira Matsuo Rie Komori Noriaki Nagai Tetsushi Yamamoto Shozo Nishida |
| author_sort | Masanobu Tsubaki |
| collection | DOAJ |
| description | Abstract Background Chronic myeloid leukemia is associated with a more favorable prognosis following treatment with BCR::ABL1 tyrosine kinase inhibitors (TKIs). Nonetheless, about 40% of affected individuals with CML display resistance or intolerance towards BCR::ABL1 TKIs. Heat shock protein 90 (HSP90) functions as a molecular chaperone and is known for its overexpression in various types of cancer, thereby HSP90 is a potential candidate for the treatment of BCR::ABL1 TKI-resistant and -sensitive CML. In present study, we aimed to investigate whether HSP90 inhibitors promote cell death in imatinib-resistant and -sensitive CML cells. Results KW-2478 and NVP-AUY922, which are HSP90 inhibitors, promoted cell death in both imatinib-resistant and -sensitive CML cells. Imatinib-resistant cells showed greater sensitivity to HSP90 inhibitors in comparison to imatinib-sensitive cells. KW-2478 inhibited the activation of Akt, extracellular regulated protein kinase 1/2, and c-Jun N-terminal kinase 1/2 in imatinib-resistant and -sensitive CML cells by promoting Met and BCR::ABL1 degradation. Conclusion These findings indicate inhibition of HSP90 such as KW-2478 and NVP-AUY922 as potential candidates for CML therapy. |
| format | Article |
| id | doaj-art-ef769f025baa48c4a5702725b9c7f3e0 |
| institution | Kabale University |
| issn | 2314-7253 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | Future Journal of Pharmaceutical Sciences |
| spelling | doaj-art-ef769f025baa48c4a5702725b9c7f3e02025-02-02T12:12:08ZengSpringerOpenFuture Journal of Pharmaceutical Sciences2314-72532025-01-0111111110.1186/s43094-025-00767-wHSP90 inhibitors promote cell death by degrading Met and BCR::ABL1 in both imatinib-resistant and -sensitive chronic myeloid leukemia cellsMasanobu Tsubaki0Taira Matsuo1Rie Komori2Noriaki Nagai3Tetsushi Yamamoto4Shozo Nishida5Laboratory of Pharmacotherapy, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri UniversityLaboratory of Pharmacotherapy, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri UniversityLaboratory of Pharmacotherapy, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri UniversityDepertment of Pharmacy, Kindai UniversityDepertment of Pharmacy, Kindai UniversityDepertment of Pharmacy, Kindai UniversityAbstract Background Chronic myeloid leukemia is associated with a more favorable prognosis following treatment with BCR::ABL1 tyrosine kinase inhibitors (TKIs). Nonetheless, about 40% of affected individuals with CML display resistance or intolerance towards BCR::ABL1 TKIs. Heat shock protein 90 (HSP90) functions as a molecular chaperone and is known for its overexpression in various types of cancer, thereby HSP90 is a potential candidate for the treatment of BCR::ABL1 TKI-resistant and -sensitive CML. In present study, we aimed to investigate whether HSP90 inhibitors promote cell death in imatinib-resistant and -sensitive CML cells. Results KW-2478 and NVP-AUY922, which are HSP90 inhibitors, promoted cell death in both imatinib-resistant and -sensitive CML cells. Imatinib-resistant cells showed greater sensitivity to HSP90 inhibitors in comparison to imatinib-sensitive cells. KW-2478 inhibited the activation of Akt, extracellular regulated protein kinase 1/2, and c-Jun N-terminal kinase 1/2 in imatinib-resistant and -sensitive CML cells by promoting Met and BCR::ABL1 degradation. Conclusion These findings indicate inhibition of HSP90 such as KW-2478 and NVP-AUY922 as potential candidates for CML therapy.https://doi.org/10.1186/s43094-025-00767-wChronic myeloid leukemiaHSP90Imatinib resistanceBCR::ABL1MetDegradation |
| spellingShingle | Masanobu Tsubaki Taira Matsuo Rie Komori Noriaki Nagai Tetsushi Yamamoto Shozo Nishida HSP90 inhibitors promote cell death by degrading Met and BCR::ABL1 in both imatinib-resistant and -sensitive chronic myeloid leukemia cells Future Journal of Pharmaceutical Sciences Chronic myeloid leukemia HSP90 Imatinib resistance BCR::ABL1 Met Degradation |
| title | HSP90 inhibitors promote cell death by degrading Met and BCR::ABL1 in both imatinib-resistant and -sensitive chronic myeloid leukemia cells |
| title_full | HSP90 inhibitors promote cell death by degrading Met and BCR::ABL1 in both imatinib-resistant and -sensitive chronic myeloid leukemia cells |
| title_fullStr | HSP90 inhibitors promote cell death by degrading Met and BCR::ABL1 in both imatinib-resistant and -sensitive chronic myeloid leukemia cells |
| title_full_unstemmed | HSP90 inhibitors promote cell death by degrading Met and BCR::ABL1 in both imatinib-resistant and -sensitive chronic myeloid leukemia cells |
| title_short | HSP90 inhibitors promote cell death by degrading Met and BCR::ABL1 in both imatinib-resistant and -sensitive chronic myeloid leukemia cells |
| title_sort | hsp90 inhibitors promote cell death by degrading met and bcr abl1 in both imatinib resistant and sensitive chronic myeloid leukemia cells |
| topic | Chronic myeloid leukemia HSP90 Imatinib resistance BCR::ABL1 Met Degradation |
| url | https://doi.org/10.1186/s43094-025-00767-w |
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