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Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer

Ultrasound (US) is a non-ionizing pressure wave that can produce mechanical and thermal effects. Bisphosphonates have demonstrated clinical utility in bone metastases treatment. Preclinical studies suggest that bisphosphonates have anticancer activity. However, bisphosphonates exhibit a high affinit...

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Autores principales: Tardoski, Sophie, Ngo, Jacqueline, Gineyts, Evelyne, Roux, Jean-Paul, Clézardin, Philippe, Melodelima, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649676/
https://www.ncbi.nlm.nih.gov/pubmed/26578234
http://dx.doi.org/10.1038/srep16354
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author Tardoski, Sophie
Ngo, Jacqueline
Gineyts, Evelyne
Roux, Jean-Paul
Clézardin, Philippe
Melodelima, David
author_facet Tardoski, Sophie
Ngo, Jacqueline
Gineyts, Evelyne
Roux, Jean-Paul
Clézardin, Philippe
Melodelima, David
author_sort Tardoski, Sophie
collection PubMed
description Ultrasound (US) is a non-ionizing pressure wave that can produce mechanical and thermal effects. Bisphosphonates have demonstrated clinical utility in bone metastases treatment. Preclinical studies suggest that bisphosphonates have anticancer activity. However, bisphosphonates exhibit a high affinity for bone mineral, which reduces their bioavailibity for tumor cells. Ultrasound has been shown to be effective for drug delivery but in interaction with gas bubbles or encapsulated drugs. We examined the effects of a clinically relevant dose of bisphosphonate zoledronate (ZOL) in combination with US. In a bone metastasis model, mice treated with ZOL+US had osteolytic lesions that were 58% smaller than those of ZOL-treated animals as well as a reduced skeletal tumor burden. In a model of primary tumors, ZOL+US treatment reduced by 42% the tumor volume, compared with ZOL-treated animals. Using a fluorescent bisphosphonate, we demonstrated that US forced the release of bisphosphonate from the bone surface, enabling a continuous impregnation of the bone marrow. Additionally, US forced the penetration of ZOL within tumors, as demonstrated by the intratumoral accumulation of unprenylated Rap1A, a surrogate marker of ZOL antitumor activity. Our findings made US a promising modality to trigger bisphosphonate anticancer activity in bone metastases and in primary tumors.
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spelling pubmed-46496762015-11-23 Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer Tardoski, Sophie Ngo, Jacqueline Gineyts, Evelyne Roux, Jean-Paul Clézardin, Philippe Melodelima, David Sci Rep Article Ultrasound (US) is a non-ionizing pressure wave that can produce mechanical and thermal effects. Bisphosphonates have demonstrated clinical utility in bone metastases treatment. Preclinical studies suggest that bisphosphonates have anticancer activity. However, bisphosphonates exhibit a high affinity for bone mineral, which reduces their bioavailibity for tumor cells. Ultrasound has been shown to be effective for drug delivery but in interaction with gas bubbles or encapsulated drugs. We examined the effects of a clinically relevant dose of bisphosphonate zoledronate (ZOL) in combination with US. In a bone metastasis model, mice treated with ZOL+US had osteolytic lesions that were 58% smaller than those of ZOL-treated animals as well as a reduced skeletal tumor burden. In a model of primary tumors, ZOL+US treatment reduced by 42% the tumor volume, compared with ZOL-treated animals. Using a fluorescent bisphosphonate, we demonstrated that US forced the release of bisphosphonate from the bone surface, enabling a continuous impregnation of the bone marrow. Additionally, US forced the penetration of ZOL within tumors, as demonstrated by the intratumoral accumulation of unprenylated Rap1A, a surrogate marker of ZOL antitumor activity. Our findings made US a promising modality to trigger bisphosphonate anticancer activity in bone metastases and in primary tumors. Nature Publishing Group 2015-11-18 /pmc/articles/PMC4649676/ /pubmed/26578234 http://dx.doi.org/10.1038/srep16354 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Tardoski, Sophie
Ngo, Jacqueline
Gineyts, Evelyne
Roux, Jean-Paul
Clézardin, Philippe
Melodelima, David
Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer
title Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer
title_full Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer
title_fullStr Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer
title_full_unstemmed Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer
title_short Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer
title_sort low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649676/
https://www.ncbi.nlm.nih.gov/pubmed/26578234
http://dx.doi.org/10.1038/srep16354
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