Anti-??-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy.

ABSTRACT: Our previous studies showed that anti-?2M monoclonal antibodies (mAbs) have strong and direct apoptotic effects on multiple myeloma (MM) cells, suggesting that anti-?2M mAbs might be developed as a novel therapeutic agent. In this study, we investigated the anti-MM effects of combination treatment with anti-?2M mAbs and bortezomib (BTZ). Our results showed that anti-?2M 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 ?2M on MM cells. BTZ up-regulated the expression of autophagy proteins, whereas combination with anti-?2M mAbs inhibited autophagy. Sequence analysis of the promoter region of beclin 1 identified 3 putative NF-?B-binding sites from -615 to -789 bp. BTZ treatment increased, whereas combination with anti-?2M mAbs reduced, NF-?B transcription activities in MM cells, and combination treatment inhibited NF-?B p65 binding to the beclin 1 promoter. Furthermore, anti-?2M 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-?2M mAb and BTZ combination treatment to overcome BTZ drug resistance and improve MM patient survival.

SUBMITTER: Zhang M 

PROVIDER: S-EPMC4496167 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature