Anti-tumor activity of a novel proteasome inhibitor D395 against multiple myeloma and its lower cardiotoxicity compared with carfilzomib

Xuxing Shen,Jianyong Li,Qing Yan,Lijuan Chen,Lina Zhang,Haoyang Zhang,Yongqiang Zhu,Chao Wu,Ye Yang,Xueyuan Wang,Meng Lei

doi:10.1038/s41419-021-03701-z

Abstract

Carfilzomib, a second-generation proteasome inhibitor, has significantly improved the survival rate of multiple myeloma (MM) patients, but its clinical application is still restricted by drug resistance and cardiotoxicity. Here, we identified a novel proteasome inhibitor, D395, and assessed its efficacy in treating MM as well as its cardiotoxicity at the preclinical level. The activities of purified and intracellular proteasomes were measured to determine the effect of D395 on the proteasome. CCK-8 and flow cytometry experiments were designed to evaluate the effects of D395 on cell growth and apoptosis. The effects of D395 and carfilzomib on serum enzyme activity, echocardiography features, cardiomyocyte morphology, and hERG channels were also compared. In our study, D395 was highly cytotoxic to MM cell lines and primary MM cells but not normal cells, and it was well tolerated in vivo. Similar to carfilzomib, D395 inhibited osteoclast differentiation in a dose-dependent manner. In particular, D395 exhibited lower cardiotoxicity than carfilzomib in all experiments. In conclusion, D395 is a novel irreversible proteasome inhibitor that has remarkable anti-MM activity and mild cardiotoxicity in vitro and in vivo.

Highlights

Multiple myeloma (MM), which is characterized by clonal proliferation of plasma cells in the bone marrow (BM), constitutes more than 10% of hematological malignancies[1,2]
Our results suggested that the CT-L, C-L, and T-L activities were lower in the carfilzomib and D395 groups than in the control group, Fig. 3 D395 induces MM cell apoptosis and inhibits the cell cycle
We demonstrated that the CT-L activities of subunits β5c (c20s) and β5i (i20s) were inhibited by both D395 and carfilzomib, and the inhibitory effect was more pronounced with the D395 treatment

Summary

Introduction

Multiple myeloma (MM), which is characterized by clonal proliferation of plasma cells in the bone marrow (BM), constitutes more than 10% of hematological malignancies[1,2]. Patients with MM usually had poor outcomes. The advent of proteasome inhibitors (PIs) has significantly improved the progression-free survival (PFS) and overall survival (OS) of patients with MM3. The proteasome degrades misassembled and misfolded proteins as well as short-lived elements such as signaling peptides that control vital activities, thereby. Carfilzomib is a second-generation PI approved for patients with relapsed/refractory multiple myeloma (RRMM)[9]. Carfilzomib is routinely combined with dexamethasone (Kd) or lenalidomide and dexamethasone (KRd) to treat RRMM. A previous study by Dimopoulos MA et al compared Kd versus bortezomib plus dexamethasone (Vd) and reported longer PFS

Methods

Results

Conclusion