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Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells

BACKGROUND: The molecular chaperone, heat shock protein 90 (Hsp90) has been shown to be overexpressed in a number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately, results with N-terminal inhibitors from initial clinical trials have been disappoi...

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Autores principales: Eskew, Jeffery D, Sadikot, Takrima, Morales, Pedro, Duren, Alicia, Dunwiddie, Irene, Swink, Megan, Zhang, Xiaoying, Hembruff, Stacey, Donnelly, Alison, Rajewski, Roger A, Blagg, Brian SJ, Manjarrez, Jacob R, Matts, Robert L, Holzbeierlein, Jeffrey M, Vielhauer, George A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3240935/
https://www.ncbi.nlm.nih.gov/pubmed/22039910
http://dx.doi.org/10.1186/1471-2407-11-468
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author Eskew, Jeffery D
Sadikot, Takrima
Morales, Pedro
Duren, Alicia
Dunwiddie, Irene
Swink, Megan
Zhang, Xiaoying
Hembruff, Stacey
Donnelly, Alison
Rajewski, Roger A
Blagg, Brian SJ
Manjarrez, Jacob R
Matts, Robert L
Holzbeierlein, Jeffrey M
Vielhauer, George A
author_facet Eskew, Jeffery D
Sadikot, Takrima
Morales, Pedro
Duren, Alicia
Dunwiddie, Irene
Swink, Megan
Zhang, Xiaoying
Hembruff, Stacey
Donnelly, Alison
Rajewski, Roger A
Blagg, Brian SJ
Manjarrez, Jacob R
Matts, Robert L
Holzbeierlein, Jeffrey M
Vielhauer, George A
author_sort Eskew, Jeffery D
collection PubMed
description BACKGROUND: The molecular chaperone, heat shock protein 90 (Hsp90) has been shown to be overexpressed in a number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately, results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance resulting from induction of the heat shock response (HSR) has led to both scheduling and administration concerns. Therefore, Hsp90 inhibitors that do not induce the heat shock response represent a promising new direction for the treatment of prostate cancer. Herein, the development of a C-terminal Hsp90 inhibitor, KU174, is described, which demonstrates anti-cancer activity in prostate cancer cells in the absence of a HSR and describe a novel approach to characterize Hsp90 inhibition in cancer cells. METHODS: PC3-MM2 and LNCaP-LN3 cells were used in both direct and indirect in vitro Hsp90 inhibition assays (DARTS, Surface Plasmon Resonance, co-immunoprecipitation, luciferase, Western blot, anti-proliferative, cytotoxicity and size exclusion chromatography) to characterize the effects of KU174 in prostate cancer cells. Pilot in vivo efficacy studies were also conducted with KU174 in PC3-MM2 xenograft studies. RESULTS: KU174 exhibits robust anti-proliferative and cytotoxic activity along with client protein degradation and disruption of Hsp90 native complexes without induction of a HSR. Furthermore, KU174 demonstrates direct binding to the Hsp90 protein and Hsp90 complexes in cancer cells. In addition, in pilot in-vivo proof-of-concept studies KU174 demonstrates efficacy at 75 mg/kg in a PC3-MM2 rat tumor model. CONCLUSIONS: Overall, these findings suggest C-terminal Hsp90 inhibitors have potential as therapeutic agents for the treatment of prostate cancer.
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spelling pubmed-32409352011-12-17 Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells Eskew, Jeffery D Sadikot, Takrima Morales, Pedro Duren, Alicia Dunwiddie, Irene Swink, Megan Zhang, Xiaoying Hembruff, Stacey Donnelly, Alison Rajewski, Roger A Blagg, Brian SJ Manjarrez, Jacob R Matts, Robert L Holzbeierlein, Jeffrey M Vielhauer, George A BMC Cancer Research Article BACKGROUND: The molecular chaperone, heat shock protein 90 (Hsp90) has been shown to be overexpressed in a number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately, results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance resulting from induction of the heat shock response (HSR) has led to both scheduling and administration concerns. Therefore, Hsp90 inhibitors that do not induce the heat shock response represent a promising new direction for the treatment of prostate cancer. Herein, the development of a C-terminal Hsp90 inhibitor, KU174, is described, which demonstrates anti-cancer activity in prostate cancer cells in the absence of a HSR and describe a novel approach to characterize Hsp90 inhibition in cancer cells. METHODS: PC3-MM2 and LNCaP-LN3 cells were used in both direct and indirect in vitro Hsp90 inhibition assays (DARTS, Surface Plasmon Resonance, co-immunoprecipitation, luciferase, Western blot, anti-proliferative, cytotoxicity and size exclusion chromatography) to characterize the effects of KU174 in prostate cancer cells. Pilot in vivo efficacy studies were also conducted with KU174 in PC3-MM2 xenograft studies. RESULTS: KU174 exhibits robust anti-proliferative and cytotoxic activity along with client protein degradation and disruption of Hsp90 native complexes without induction of a HSR. Furthermore, KU174 demonstrates direct binding to the Hsp90 protein and Hsp90 complexes in cancer cells. In addition, in pilot in-vivo proof-of-concept studies KU174 demonstrates efficacy at 75 mg/kg in a PC3-MM2 rat tumor model. CONCLUSIONS: Overall, these findings suggest C-terminal Hsp90 inhibitors have potential as therapeutic agents for the treatment of prostate cancer. BioMed Central 2011-10-31 /pmc/articles/PMC3240935/ /pubmed/22039910 http://dx.doi.org/10.1186/1471-2407-11-468 Text en Copyright ©2011 Eskew et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Eskew, Jeffery D
Sadikot, Takrima
Morales, Pedro
Duren, Alicia
Dunwiddie, Irene
Swink, Megan
Zhang, Xiaoying
Hembruff, Stacey
Donnelly, Alison
Rajewski, Roger A
Blagg, Brian SJ
Manjarrez, Jacob R
Matts, Robert L
Holzbeierlein, Jeffrey M
Vielhauer, George A
Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells
title Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells
title_full Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells
title_fullStr Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells
title_full_unstemmed Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells
title_short Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells
title_sort development and characterization of a novel c-terminal inhibitor of hsp90 in androgen dependent and independent prostate cancer cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3240935/
https://www.ncbi.nlm.nih.gov/pubmed/22039910
http://dx.doi.org/10.1186/1471-2407-11-468
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