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Synthesis of a Bone-Targeted Bortezomib with In Vivo Anti-Myeloma Effects in Mice
Multiple myeloma (MM) is the most common cancer affecting the bone and bone marrow and remains incurable for most patients; novel therapies are therefore needed. Bortezomib (Btz) is an FDA-approved drug for the treatment of patients with MM. However, its severe side effects require a dose reduction...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161102/ https://www.ncbi.nlm.nih.gov/pubmed/30201882 http://dx.doi.org/10.3390/pharmaceutics10030154 |
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author | Wang, Hua Xiao, Lifeng Tao, Jianguo Srinivasan, Venkat Boyce, Brendan F. Ebetino, Frank H. Oyajobi, Babatunde O. Boeckman, Robert K. Xing, Lianping |
author_facet | Wang, Hua Xiao, Lifeng Tao, Jianguo Srinivasan, Venkat Boyce, Brendan F. Ebetino, Frank H. Oyajobi, Babatunde O. Boeckman, Robert K. Xing, Lianping |
author_sort | Wang, Hua |
collection | PubMed |
description | Multiple myeloma (MM) is the most common cancer affecting the bone and bone marrow and remains incurable for most patients; novel therapies are therefore needed. Bortezomib (Btz) is an FDA-approved drug for the treatment of patients with MM. However, its severe side effects require a dose reduction or the potential discontinuation of treatment. To overcome this limitation, we conjugated Btz to a bisphosphonate (BP) residue lacking anti-osteoclastic activity using a novel chemical linker and generated a new bone-targeted Btz-based (BP-Btz) proteasome inhibitor. We demonstrated that BP-Btz, but not Btz, bound to bone slices and inhibited the growth of MM cells in vitro. In a mouse model of MM, BP-Btz more effectively reduced tumor burden and bone loss with less systemic side effects than Btz. Thus, BP-Btz may represent a novel therapeutic approach to treat patients with MM. |
format | Online Article Text |
id | pubmed-6161102 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-61611022018-10-01 Synthesis of a Bone-Targeted Bortezomib with In Vivo Anti-Myeloma Effects in Mice Wang, Hua Xiao, Lifeng Tao, Jianguo Srinivasan, Venkat Boyce, Brendan F. Ebetino, Frank H. Oyajobi, Babatunde O. Boeckman, Robert K. Xing, Lianping Pharmaceutics Article Multiple myeloma (MM) is the most common cancer affecting the bone and bone marrow and remains incurable for most patients; novel therapies are therefore needed. Bortezomib (Btz) is an FDA-approved drug for the treatment of patients with MM. However, its severe side effects require a dose reduction or the potential discontinuation of treatment. To overcome this limitation, we conjugated Btz to a bisphosphonate (BP) residue lacking anti-osteoclastic activity using a novel chemical linker and generated a new bone-targeted Btz-based (BP-Btz) proteasome inhibitor. We demonstrated that BP-Btz, but not Btz, bound to bone slices and inhibited the growth of MM cells in vitro. In a mouse model of MM, BP-Btz more effectively reduced tumor burden and bone loss with less systemic side effects than Btz. Thus, BP-Btz may represent a novel therapeutic approach to treat patients with MM. MDPI 2018-09-10 /pmc/articles/PMC6161102/ /pubmed/30201882 http://dx.doi.org/10.3390/pharmaceutics10030154 Text en © 2018 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Wang, Hua Xiao, Lifeng Tao, Jianguo Srinivasan, Venkat Boyce, Brendan F. Ebetino, Frank H. Oyajobi, Babatunde O. Boeckman, Robert K. Xing, Lianping Synthesis of a Bone-Targeted Bortezomib with In Vivo Anti-Myeloma Effects in Mice |
title | Synthesis of a Bone-Targeted Bortezomib with In Vivo Anti-Myeloma Effects in Mice |
title_full | Synthesis of a Bone-Targeted Bortezomib with In Vivo Anti-Myeloma Effects in Mice |
title_fullStr | Synthesis of a Bone-Targeted Bortezomib with In Vivo Anti-Myeloma Effects in Mice |
title_full_unstemmed | Synthesis of a Bone-Targeted Bortezomib with In Vivo Anti-Myeloma Effects in Mice |
title_short | Synthesis of a Bone-Targeted Bortezomib with In Vivo Anti-Myeloma Effects in Mice |
title_sort | synthesis of a bone-targeted bortezomib with in vivo anti-myeloma effects in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161102/ https://www.ncbi.nlm.nih.gov/pubmed/30201882 http://dx.doi.org/10.3390/pharmaceutics10030154 |
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