Abstract
Our previous studies showed that anti-β2M monoclonal antibodies (mAbs) have strong and direct apoptotic effects on multiple myeloma (MM) cells, suggesting that anti-β2M mAbs might be developed as a novel therapeutic agent. In this study, we investigated the anti-MM effects of combination treatment with anti-β2M mAbs and bortezomib (BTZ). Our results showed that anti-β2M 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 β2M on MM cells. BTZ up-regulated the expression of autophagy proteins, whereas combination with anti-β2M 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-β2M mAbs reduced, NF-κB transcription activities in MM cells, and combination treatment inhibited NF-κB p65 binding to the beclin 1 promoter. Furthermore, anti-β2M 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-β2M mAb and BTZ combination treatment to overcome BTZ drug resistance and improve MM patient survival.
Keywords:
NF-κ p65; anti-β2M monoclonal antibody; autophagy; bortezomib; multiple myeloma.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology*
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins / biosynthesis
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Apoptosis Regulatory Proteins / genetics
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Autophagy / drug effects*
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Beclin-1
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Bortezomib / pharmacology*
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / physiology
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Drug Screening Assays, Antitumor
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Drug Synergism
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Humans
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Lysosomal Membrane Proteins / biosynthesis
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Lysosomal Membrane Proteins / genetics
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Male
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics
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Mice
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Mice, SCID
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Microtubule-Associated Proteins / biosynthesis
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Microtubule-Associated Proteins / genetics
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / immunology
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RNA, Bacterial
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RNA, Small Interfering / genetics
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Signal Transduction / drug effects
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Transcription Factor RelA / antagonists & inhibitors
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
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beta 2-Microglobulin / antagonists & inhibitors*
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beta 2-Microglobulin / biosynthesis
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beta 2-Microglobulin / genetics
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beta 2-Microglobulin / immunology
Substances
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Antibodies, Monoclonal
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Apoptosis Regulatory Proteins
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BECN1 protein, human
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Beclin-1
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LAMP1 protein, human
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Lysosomal Membrane Proteins
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MAP1LC3B protein, human
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Membrane Proteins
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Microtubule-Associated Proteins
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Neoplasm Proteins
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RELA protein, human
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RNA I
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RNA, Bacterial
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RNA, Small Interfering
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Transcription Factor RelA
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beta 2-Microglobulin
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Bortezomib