Abstract:
:Proteasome inhibition demonstrates highly effective impact on multiple myeloma (MM) treatment. Here, we aimed to examine anti-tumor efficiency and underlying mechanisms of a novel well tolerated orally applicable proteasome inhibitor NNU546 and its hydrolyzed pharmacologically active form NNU219. NNU219 showed more selective inhibition to proteasome catalytic subunits and less off-target effect than bortezomib ex vivo. Moreover, intravenous and oral administration of either NNU219 or NNU546 led to more sustained pharmacodynamic inhibitions of proteasome activities compared with bortezomib. Importantly, NNU219 exhibited potential anti-MM activity in both MM cell lines and primary samples in vitro. The anti-MM activity of NNU219 was associated with induction of G2/M-phase arrest and apoptosis via activation of the caspase cascade and endoplasmic reticulum stress response. Significant growth-inhibitory effects of NNU219 and NNU546 were observed in 3 different human MM xenograft mouse models. Furthermore, such observation was even found in the presence of a bone marrow microenvironment. Taken together, these findings provided the basis for clinical trial of NNU546 to determine its potential as a candidate for MM treatment.
journal_name
Aging (Albany NY)journal_title
Agingauthors
Zhou H,Lei M,Wang W,Guo M,Wang J,Zhang H,Qiao L,Feng H,Liu Z,Chen L,Hou J,Wang X,Gu C,Zhao B,Izumchenko E,Yang Y,Zhu Ydoi
10.18632/aging.104023subject
Has Abstractpub_date
2020-11-16 00:00:00pages
22949-22974issue
22issn
1945-4589pii
104023journal_volume
12pub_type
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