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Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model

Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the f...

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Autores principales: Suominen, Mari I., Mäki-Jouppila, Jenni, Huhtinen, Anna, Sjöholm, Birgitta, Rissanen, Jukka P., Luostarinen, Anniina, Fagerlund, Katja M., Alhoniemi, Esa, Siemeister, Gerhard, Mumberg, Dominik, Käkönen, Sanna-Maria, Scholz, Arne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197539/
https://www.ncbi.nlm.nih.gov/pubmed/34070363
http://dx.doi.org/10.3390/ijms22115570
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author Suominen, Mari I.
Mäki-Jouppila, Jenni
Huhtinen, Anna
Sjöholm, Birgitta
Rissanen, Jukka P.
Luostarinen, Anniina
Fagerlund, Katja M.
Alhoniemi, Esa
Siemeister, Gerhard
Mumberg, Dominik
Käkönen, Sanna-Maria
Scholz, Arne
author_facet Suominen, Mari I.
Mäki-Jouppila, Jenni
Huhtinen, Anna
Sjöholm, Birgitta
Rissanen, Jukka P.
Luostarinen, Anniina
Fagerlund, Katja M.
Alhoniemi, Esa
Siemeister, Gerhard
Mumberg, Dominik
Käkönen, Sanna-Maria
Scholz, Arne
author_sort Suominen, Mari I.
collection PubMed
description Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis. We hypothesized that radium-223 and bortezomib combination treatment would have additive effects on MM. In vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy. In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and radium-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone. Bortezomib decreased the number of osteoclasts at the tumor–bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts. Furthermore, the combination therapy improved the incorporation of radium-223 into MM-bearing bone. Importantly, the combination therapy decreased tumor burden and restored body weights in MM mice. These results suggest that the combination of radium-223 with bortezomib could constitute a novel, effective therapy for MM and, in particular, myeloma bone disease.
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spelling pubmed-81975392021-06-13 Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model Suominen, Mari I. Mäki-Jouppila, Jenni Huhtinen, Anna Sjöholm, Birgitta Rissanen, Jukka P. Luostarinen, Anniina Fagerlund, Katja M. Alhoniemi, Esa Siemeister, Gerhard Mumberg, Dominik Käkönen, Sanna-Maria Scholz, Arne Int J Mol Sci Article Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis. We hypothesized that radium-223 and bortezomib combination treatment would have additive effects on MM. In vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy. In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and radium-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone. Bortezomib decreased the number of osteoclasts at the tumor–bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts. Furthermore, the combination therapy improved the incorporation of radium-223 into MM-bearing bone. Importantly, the combination therapy decreased tumor burden and restored body weights in MM mice. These results suggest that the combination of radium-223 with bortezomib could constitute a novel, effective therapy for MM and, in particular, myeloma bone disease. MDPI 2021-05-25 /pmc/articles/PMC8197539/ /pubmed/34070363 http://dx.doi.org/10.3390/ijms22115570 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Suominen, Mari I.
Mäki-Jouppila, Jenni
Huhtinen, Anna
Sjöholm, Birgitta
Rissanen, Jukka P.
Luostarinen, Anniina
Fagerlund, Katja M.
Alhoniemi, Esa
Siemeister, Gerhard
Mumberg, Dominik
Käkönen, Sanna-Maria
Scholz, Arne
Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model
title Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model
title_full Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model
title_fullStr Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model
title_full_unstemmed Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model
title_short Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model
title_sort additive benefits of radium-223 dichloride and bortezomib combination in a systemic multiple myeloma mouse model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197539/
https://www.ncbi.nlm.nih.gov/pubmed/34070363
http://dx.doi.org/10.3390/ijms22115570
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