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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c293a04a3a7f4e7ea36a495332a1bd11
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spelling	oai:doaj.org-article:c293a04a3a7f4e7ea36a495332a1bd112021-12-02T16:08:21ZAnti-leukemia activity of a Hsp70 inhibitor and its hybrid molecules10.1038/s41598-017-03814-62045-2322https://doaj.org/article/c293a04a3a7f4e7ea36a495332a1bd112017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03814-6https://doaj.org/toc/2045-2322Abstract 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.Seong-Hyun ParkWon-Je KimHui LiWonil SeoSang-Hyun ParkHwan KimSang Chul ShinErik R. P. ZuiderwegEunice EunKyeong KimTaebo SimNak-Kyoon KimInjae ShinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
title	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_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_sort	anti-leukemia activity of a hsp70 inhibitor and its hybrid molecules
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/c293a04a3a7f4e7ea36a495332a1bd11
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Anti-leukemia activity of a Hsp70 inhibitor and its hybrid molecules

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