Research Paper Volume 12, Issue 22 pp 22949—22974
In vitro and in vivo efficacy of the novel oral proteasome inhibitor NNU546 in multiple myeloma
- 1 College of Life Science, Nanjing Normal University, Nanjing 210046, PR China
- 2 College of Science, Nanjing Forestry University, Nanjing 210037, PR China
- 3 School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
- 4 Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., Nanjing 210046, PR China
- 5 The 1st Affiliated Hospital of Nanjing Medical University, Nanjing 210029, PR China
- 6 School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210046, PR China
- 7 Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL 60637, USA
- 8 The 3rd Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
Received: June 17, 2020 Accepted: August 15, 2020 Published: November 16, 2020
https://doi.org/10.18632/aging.104023How to Cite
Copyright: © 2020 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.
Abbreviations
UPP: ubiquitin-proteasome pathway; MM: multiple myeloma; MCL: mantle cell lymphoma; CT-L: chymotrypsin-like; C-L: caspase-like; ER: endoplasmic reticulum; BM: bone marrow; PDX: patient-derived xenograft model; PBMCs: Peripheral blood mononuclear cells; T-L: trypsin-like; cCP: constitutive 20S proteasomes; iCP: 20S immunoproteasome; TNF-α: tumor necrosis factor-α; PN: peripheral neurotoxicity; SAEs: serious adverse events.