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CDK5 inhibition in vitro and in vivo induces cell death in myeloma and overcomes the obstacle of bortezomib resistance

The emergence of new drugs is a major feature of the treatment history of multiple myeloma (MM), which also reflects the current incurability of MM. As a unique member of cyclin dependent kinase (CDK) family, CDK5 participates in numerous tumorigenic or non-tumorigenic processes. The aim of this stu...

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Autores principales: Tang, Hailong, Xu, Li, Cen, Xi, Yang, Li, Feng, Juan, Li, Guang, Zhu, Huafeng, Gao, Shan, Yu, Yan, Zhao, Yaping, Tian, Zhiqiang, Hou, Liping, Yu, Shuchun, Gao, Guangxun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169959/
https://www.ncbi.nlm.nih.gov/pubmed/32236619
http://dx.doi.org/10.3892/ijmm.2020.4553
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author Tang, Hailong
Xu, Li
Cen, Xi
Yang, Li
Feng, Juan
Li, Guang
Zhu, Huafeng
Gao, Shan
Yu, Yan
Zhao, Yaping
Tian, Zhiqiang
Hou, Liping
Yu, Shuchun
Gao, Guangxun
author_facet Tang, Hailong
Xu, Li
Cen, Xi
Yang, Li
Feng, Juan
Li, Guang
Zhu, Huafeng
Gao, Shan
Yu, Yan
Zhao, Yaping
Tian, Zhiqiang
Hou, Liping
Yu, Shuchun
Gao, Guangxun
author_sort Tang, Hailong
collection PubMed
description The emergence of new drugs is a major feature of the treatment history of multiple myeloma (MM), which also reflects the current incurability of MM. As a unique member of cyclin dependent kinase (CDK) family, CDK5 participates in numerous tumorigenic or non-tumorigenic processes. The aim of this study is to investigate the effects of CDK5 on the viability of MM cells and bortezomib resistance using western blotting, immunohistochemistry, transient transfection, MTT assays, cell cycle analysis, apoptosis assays and a myeloma xenograft mouse model. The present study found that MM patients with high CDK5 expression in the bone marrow do not respond well to bortezomib, have higher DS stage and worse prognosis. Genetic and pharmacological (dinaciclib) inhibition of CDK5 triggers MM cell viability inhibition. Dinaciclib induces G2/M arrest and apoptosis of MM cells. In vivo experiments with myeloma xenograft mice indicate that dinaciclib significantly reduces the volume of tumors with good tolerance. Dinaciclib combined with bortezomib exerts a synergistic anti-myeloma activity accompanied by inhibiting the activation of the nuclear factor-κB pathway. This study demonstrates the important role of CDK5 in the pathogenesis, viability, prognosis and resistance to bortezomib of MM, laying a solid theoretical foundation for further clinical use of CDK5 inhibitors.
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spelling pubmed-71699592020-04-24 CDK5 inhibition in vitro and in vivo induces cell death in myeloma and overcomes the obstacle of bortezomib resistance Tang, Hailong Xu, Li Cen, Xi Yang, Li Feng, Juan Li, Guang Zhu, Huafeng Gao, Shan Yu, Yan Zhao, Yaping Tian, Zhiqiang Hou, Liping Yu, Shuchun Gao, Guangxun Int J Mol Med Articles The emergence of new drugs is a major feature of the treatment history of multiple myeloma (MM), which also reflects the current incurability of MM. As a unique member of cyclin dependent kinase (CDK) family, CDK5 participates in numerous tumorigenic or non-tumorigenic processes. The aim of this study is to investigate the effects of CDK5 on the viability of MM cells and bortezomib resistance using western blotting, immunohistochemistry, transient transfection, MTT assays, cell cycle analysis, apoptosis assays and a myeloma xenograft mouse model. The present study found that MM patients with high CDK5 expression in the bone marrow do not respond well to bortezomib, have higher DS stage and worse prognosis. Genetic and pharmacological (dinaciclib) inhibition of CDK5 triggers MM cell viability inhibition. Dinaciclib induces G2/M arrest and apoptosis of MM cells. In vivo experiments with myeloma xenograft mice indicate that dinaciclib significantly reduces the volume of tumors with good tolerance. Dinaciclib combined with bortezomib exerts a synergistic anti-myeloma activity accompanied by inhibiting the activation of the nuclear factor-κB pathway. This study demonstrates the important role of CDK5 in the pathogenesis, viability, prognosis and resistance to bortezomib of MM, laying a solid theoretical foundation for further clinical use of CDK5 inhibitors. D.A. Spandidos 2020-06 2020-03-26 /pmc/articles/PMC7169959/ /pubmed/32236619 http://dx.doi.org/10.3892/ijmm.2020.4553 Text en Copyright: © Tang et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Tang, Hailong
Xu, Li
Cen, Xi
Yang, Li
Feng, Juan
Li, Guang
Zhu, Huafeng
Gao, Shan
Yu, Yan
Zhao, Yaping
Tian, Zhiqiang
Hou, Liping
Yu, Shuchun
Gao, Guangxun
CDK5 inhibition in vitro and in vivo induces cell death in myeloma and overcomes the obstacle of bortezomib resistance
title CDK5 inhibition in vitro and in vivo induces cell death in myeloma and overcomes the obstacle of bortezomib resistance
title_full CDK5 inhibition in vitro and in vivo induces cell death in myeloma and overcomes the obstacle of bortezomib resistance
title_fullStr CDK5 inhibition in vitro and in vivo induces cell death in myeloma and overcomes the obstacle of bortezomib resistance
title_full_unstemmed CDK5 inhibition in vitro and in vivo induces cell death in myeloma and overcomes the obstacle of bortezomib resistance
title_short CDK5 inhibition in vitro and in vivo induces cell death in myeloma and overcomes the obstacle of bortezomib resistance
title_sort cdk5 inhibition in vitro and in vivo induces cell death in myeloma and overcomes the obstacle of bortezomib resistance
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169959/
https://www.ncbi.nlm.nih.gov/pubmed/32236619
http://dx.doi.org/10.3892/ijmm.2020.4553
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