Anti-leukemia activity of a Hsp70 inhibitor and its hybrid molecules
Abstract In this study we examined the anti-leukemia activity of a small molecule inhibitor of Hsp70 proteins, apoptozole (Az), and hybrids in which it is linked to an inhibitor of either Hsp90 (geldanamycin) or Abl kinase (imatinib). The results of NMR studies revealed that Az associates with an AT...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-03814-6 |
| _version_ | 1818683515983626240 |
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| author | Seong-Hyun Park Won-Je Kim Hui Li Wonil Seo Sang-Hyun Park Hwan Kim Sang Chul Shin Erik R. P. Zuiderweg Eunice EunKyeong Kim Taebo Sim Nak-Kyoon Kim Injae Shin |
| author_facet | Seong-Hyun Park Won-Je Kim Hui Li Wonil Seo Sang-Hyun Park Hwan Kim Sang Chul Shin Erik R. P. Zuiderweg Eunice EunKyeong Kim Taebo Sim Nak-Kyoon Kim Injae Shin |
| author_sort | Seong-Hyun Park |
| collection | DOAJ |
| description | Abstract In this study we examined the anti-leukemia activity of a small molecule inhibitor of Hsp70 proteins, apoptozole (Az), and hybrids in which it is linked to an inhibitor of either Hsp90 (geldanamycin) or Abl kinase (imatinib). The results of NMR studies revealed that Az associates with an ATPase domain of Hsc70 and thus blocks ATP binding to the protein. Observations made in the cell study indicated that Az treatment promotes leukemia cell death by activating caspase-dependent apoptosis without affecting the caspase-independent apoptotic pathway. Importantly, the hybrids composed of Az and geldanamycin, which have high inhibitory activities towards both Hsp70 and Hsp90, exhibit enhanced anti-leukemia activity relative to the individual inhibitors. However, the Az and imatinib hybrids have weak inhibitory activities towards Hsp70 and Abl, and display lower cytotoxicity against leukemia cells compared to those of the individual constituents. The results of a mechanistic study showed that the active hybrid molecules promote leukemia cell death through a caspase-dependent apoptotic pathway. Taken together, the findings suggest that Hsp70 inhibitors as well as their hybrids can serve as potential anti-leukemia agents. |
| first_indexed | 2024-12-17T10:35:58Z |
| format | Article |
| id | doaj.art-c293a04a3a7f4e7ea36a495332a1bd11 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-17T10:35:58Z |
| publishDate | 2017-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-c293a04a3a7f4e7ea36a495332a1bd112022-12-21T21:52:23ZengNature PortfolioScientific Reports2045-23222017-06-017111110.1038/s41598-017-03814-6Anti-leukemia activity of a Hsp70 inhibitor and its hybrid moleculesSeong-Hyun Park0Won-Je Kim1Hui Li2Wonil Seo3Sang-Hyun Park4Hwan Kim5Sang Chul Shin6Erik R. P. Zuiderweg7Eunice EunKyeong Kim8Taebo Sim9Nak-Kyoon Kim10Injae Shin11National Creative Research Initiative Center for Biofunctional Molecules, Department of Chemistry, Yonsei UniversityAdvanced Analysis Center, Korea Institute of Science and Technology (KIST)National Creative Research Initiative Center for Biofunctional Molecules, Department of Chemistry, Yonsei UniversityNational Creative Research Initiative Center for Biofunctional Molecules, Department of Chemistry, Yonsei UniversityNational Creative Research Initiative Center for Biofunctional Molecules, Department of Chemistry, Yonsei UniversityChemical Kinomics Research Center, Korea Institute of Science and Technology (KIST)Biomedical Research Institute, Korea Institute of Science and Technology (KIST)Department of Biological Chemistry, The University of MichiganBiomedical Research Institute, Korea Institute of Science and Technology (KIST)Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST)Advanced Analysis Center, Korea Institute of Science and Technology (KIST)National Creative Research Initiative Center for Biofunctional Molecules, Department of Chemistry, Yonsei UniversityAbstract In this study we examined the anti-leukemia activity of a small molecule inhibitor of Hsp70 proteins, apoptozole (Az), and hybrids in which it is linked to an inhibitor of either Hsp90 (geldanamycin) or Abl kinase (imatinib). The results of NMR studies revealed that Az associates with an ATPase domain of Hsc70 and thus blocks ATP binding to the protein. Observations made in the cell study indicated that Az treatment promotes leukemia cell death by activating caspase-dependent apoptosis without affecting the caspase-independent apoptotic pathway. Importantly, the hybrids composed of Az and geldanamycin, which have high inhibitory activities towards both Hsp70 and Hsp90, exhibit enhanced anti-leukemia activity relative to the individual inhibitors. However, the Az and imatinib hybrids have weak inhibitory activities towards Hsp70 and Abl, and display lower cytotoxicity against leukemia cells compared to those of the individual constituents. The results of a mechanistic study showed that the active hybrid molecules promote leukemia cell death through a caspase-dependent apoptotic pathway. Taken together, the findings suggest that Hsp70 inhibitors as well as their hybrids can serve as potential anti-leukemia agents.https://doi.org/10.1038/s41598-017-03814-6 |
| spellingShingle | Seong-Hyun Park Won-Je Kim Hui Li Wonil Seo Sang-Hyun Park Hwan Kim Sang Chul Shin Erik R. P. Zuiderweg Eunice EunKyeong Kim Taebo Sim Nak-Kyoon Kim Injae Shin Anti-leukemia activity of a Hsp70 inhibitor and its hybrid molecules Scientific Reports |
| title | Anti-leukemia activity of a Hsp70 inhibitor and its hybrid molecules |
| title_full | Anti-leukemia activity of a Hsp70 inhibitor and its hybrid molecules |
| title_fullStr | Anti-leukemia activity of a Hsp70 inhibitor and its hybrid molecules |
| title_full_unstemmed | Anti-leukemia activity of a Hsp70 inhibitor and its hybrid molecules |
| title_short | Anti-leukemia activity of a Hsp70 inhibitor and its hybrid molecules |
| title_sort | anti leukemia activity of a hsp70 inhibitor and its hybrid molecules |
| url | https://doi.org/10.1038/s41598-017-03814-6 |
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