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Anti-β(2)-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy

Our previous studies showed that anti-β(2)M monoclonal antibodies (mAbs) have strong and direct apoptotic effects on multiple myeloma (MM) cells, suggesting that anti-β(2)M mAbs might be developed as a novel therapeutic agent. In this study, we investigated the anti-MM effects of combination treatme...

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Autores principales: Zhang, Mingjun, He, Jin, Liu, Zhiqiang, Lu, Yong, Zheng, Yuhuan, Li, Haiyan, Xu, Jingda, Liu, Huan, Qian, Jianfei, Orlowski, Robert Z., Kwak, Larry W., Yi, Qing, Yang, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496167/
https://www.ncbi.nlm.nih.gov/pubmed/25895124
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author Zhang, Mingjun
He, Jin
Liu, Zhiqiang
Lu, Yong
Zheng, Yuhuan
Li, Haiyan
Xu, Jingda
Liu, Huan
Qian, Jianfei
Orlowski, Robert Z.
Kwak, Larry W.
Yi, Qing
Yang, Jing
author_facet Zhang, Mingjun
He, Jin
Liu, Zhiqiang
Lu, Yong
Zheng, Yuhuan
Li, Haiyan
Xu, Jingda
Liu, Huan
Qian, Jianfei
Orlowski, Robert Z.
Kwak, Larry W.
Yi, Qing
Yang, Jing
author_sort Zhang, Mingjun
collection PubMed
description Our previous studies showed that anti-β(2)M monoclonal antibodies (mAbs) have strong and direct apoptotic effects on multiple myeloma (MM) cells, suggesting that anti-β(2)M mAbs might be developed as a novel therapeutic agent. In this study, we investigated the anti-MM effects of combination treatment with anti-β(2)M mAbs and bortezomib (BTZ). Our results showed that anti-β(2)M mAbs enhanced BTZ-induced apoptosis of MM cell lines and primary MM cells. Combination treatment could also induce apoptosis of BTZ-resistant MM cells, and the enhanced effect depended on the surface expression of β(2)M on MM cells. BTZ up-regulated the expression of autophagy proteins, whereas combination with anti-β(2)M mAbs inhibited autophagy. Sequence analysis of the promoter region of beclin 1 identified 3 putative NF-κB-binding sites from –615 to –789 bp. BTZ treatment increased, whereas combination with anti-β(2)M mAbs reduced, NF-κB transcription activities in MM cells, and combination treatment inhibited NF-κB p65 binding to the beclin 1 promoter. Furthermore, anti-β(2)M mAbs and BTZ combination treatment had anti-MM activities in an established MM mouse model. Thus, our studies provide new insight and support for the clinical development of an anti-β(2)M mAb and BTZ combination treatment to overcome BTZ drug resistance and improve MM patient survival.
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spelling pubmed-44961672015-07-10 Anti-β(2)-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy Zhang, Mingjun He, Jin Liu, Zhiqiang Lu, Yong Zheng, Yuhuan Li, Haiyan Xu, Jingda Liu, Huan Qian, Jianfei Orlowski, Robert Z. Kwak, Larry W. Yi, Qing Yang, Jing Oncotarget Research Paper Our previous studies showed that anti-β(2)M monoclonal antibodies (mAbs) have strong and direct apoptotic effects on multiple myeloma (MM) cells, suggesting that anti-β(2)M mAbs might be developed as a novel therapeutic agent. In this study, we investigated the anti-MM effects of combination treatment with anti-β(2)M mAbs and bortezomib (BTZ). Our results showed that anti-β(2)M mAbs enhanced BTZ-induced apoptosis of MM cell lines and primary MM cells. Combination treatment could also induce apoptosis of BTZ-resistant MM cells, and the enhanced effect depended on the surface expression of β(2)M on MM cells. BTZ up-regulated the expression of autophagy proteins, whereas combination with anti-β(2)M mAbs inhibited autophagy. Sequence analysis of the promoter region of beclin 1 identified 3 putative NF-κB-binding sites from –615 to –789 bp. BTZ treatment increased, whereas combination with anti-β(2)M mAbs reduced, NF-κB transcription activities in MM cells, and combination treatment inhibited NF-κB p65 binding to the beclin 1 promoter. Furthermore, anti-β(2)M mAbs and BTZ combination treatment had anti-MM activities in an established MM mouse model. Thus, our studies provide new insight and support for the clinical development of an anti-β(2)M mAb and BTZ combination treatment to overcome BTZ drug resistance and improve MM patient survival. Impact Journals LLC 2015-03-31 /pmc/articles/PMC4496167/ /pubmed/25895124 Text en Copyright: © 2015 Zhang et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Zhang, Mingjun
He, Jin
Liu, Zhiqiang
Lu, Yong
Zheng, Yuhuan
Li, Haiyan
Xu, Jingda
Liu, Huan
Qian, Jianfei
Orlowski, Robert Z.
Kwak, Larry W.
Yi, Qing
Yang, Jing
Anti-β(2)-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy
title Anti-β(2)-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy
title_full Anti-β(2)-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy
title_fullStr Anti-β(2)-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy
title_full_unstemmed Anti-β(2)-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy
title_short Anti-β(2)-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy
title_sort anti-β(2)-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496167/
https://www.ncbi.nlm.nih.gov/pubmed/25895124
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