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Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR

BACKGROUND: To determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer (PCa), we investigated the relationship between the androgen receptor (AR) and mTOR pathways and the impact of inhibiting both pathways in androgen-dependent and castration-...

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Autores principales: Schayowitz, A, Sabnis, G, Goloubeva, O, Njar, V C O, Brodie, A M H
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965879/
https://www.ncbi.nlm.nih.gov/pubmed/20842117
http://dx.doi.org/10.1038/sj.bjc.6605882
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author Schayowitz, A
Sabnis, G
Goloubeva, O
Njar, V C O
Brodie, A M H
author_facet Schayowitz, A
Sabnis, G
Goloubeva, O
Njar, V C O
Brodie, A M H
author_sort Schayowitz, A
collection PubMed
description BACKGROUND: To determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer (PCa), we investigated the relationship between the androgen receptor (AR) and mTOR pathways and the impact of inhibiting both pathways in androgen-dependent and castration-resistant PCa models. EXPERIMENTAL DESIGN: Androgen-dependent (LNCaP) and castration-resistant PCa (HP-LNCaP) cells were grown as tumours in SCID mice. Once tumours reached 500 mm(3), animals were grouped and injected subcutaneous with vehicle, our novel anti-androgen/androgen synthesis inhibitor, VN/124-1, bicalutamide, and everolimus. Tumour volumes were measured biweekly. The PSA and protein analyses were performed after completion of the treatment. RESULTS: The addition of everolimus to bicalutamide treatment of resistant tumours significantly reduced tumour growth rates and tumour volumes. Anti-androgen treatment also increased protein expression of multiple signal transduction pathways earlier than vehicle-treated control xenografts. VN/124-1 plus everolimus acted in concert to reduce tumour growth rates in our castration-resistant xenograft model. CONCLUSIONS: This study suggests that dual inhibition of AR and mTOR in castration-resistant xenograft models can restore sensitivity of tumours to anti-androgen therapy. Furthermore, after bicalutamide failure, dual inhibition with VN/124-1 and everolimus was the most effective treatment.
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spelling pubmed-29658792011-09-28 Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR Schayowitz, A Sabnis, G Goloubeva, O Njar, V C O Brodie, A M H Br J Cancer Translational Therapeutics BACKGROUND: To determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer (PCa), we investigated the relationship between the androgen receptor (AR) and mTOR pathways and the impact of inhibiting both pathways in androgen-dependent and castration-resistant PCa models. EXPERIMENTAL DESIGN: Androgen-dependent (LNCaP) and castration-resistant PCa (HP-LNCaP) cells were grown as tumours in SCID mice. Once tumours reached 500 mm(3), animals were grouped and injected subcutaneous with vehicle, our novel anti-androgen/androgen synthesis inhibitor, VN/124-1, bicalutamide, and everolimus. Tumour volumes were measured biweekly. The PSA and protein analyses were performed after completion of the treatment. RESULTS: The addition of everolimus to bicalutamide treatment of resistant tumours significantly reduced tumour growth rates and tumour volumes. Anti-androgen treatment also increased protein expression of multiple signal transduction pathways earlier than vehicle-treated control xenografts. VN/124-1 plus everolimus acted in concert to reduce tumour growth rates in our castration-resistant xenograft model. CONCLUSIONS: This study suggests that dual inhibition of AR and mTOR in castration-resistant xenograft models can restore sensitivity of tumours to anti-androgen therapy. Furthermore, after bicalutamide failure, dual inhibition with VN/124-1 and everolimus was the most effective treatment. Nature Publishing Group 2010-09-28 2010-09-14 /pmc/articles/PMC2965879/ /pubmed/20842117 http://dx.doi.org/10.1038/sj.bjc.6605882 Text en Copyright © 2010 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Translational Therapeutics
Schayowitz, A
Sabnis, G
Goloubeva, O
Njar, V C O
Brodie, A M H
Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR
title Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR
title_full Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR
title_fullStr Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR
title_full_unstemmed Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR
title_short Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR
title_sort prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of ar and mtor
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965879/
https://www.ncbi.nlm.nih.gov/pubmed/20842117
http://dx.doi.org/10.1038/sj.bjc.6605882
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