Affiliation:
1. Xuzhou Medical University Blood Diseases Institute Xuzhou China
2. Xuzhou Medical University Department of Hematology Xuzhou China
Abstract
Background::
Although immunotherapies have greatly improved diffuse large B-cell
lymphoma (DLBCL) prognosis, a proportion of patients remain to be relapsed or refractory. Therefore,
the identification of novel therapeutic targets and drugs is urgently required. Inhibition of the
bromodomain and extra-terminal (BET) proteins has been a promising therapeutic strategy for
various haematologic cancers. CPI-0610 is a potent and selective BET inhibitor. The effects of
CPI-0610 in DLBCL cells have not been reported yet.
Aims::
The aim of this study was to assess the effects of CPI-0610 in DLBCL and its underlying
mechanisms.
Methods::
DLBCL cells were treated with CPI-0610, followed by measuring cell viability, cell cycle,
apoptosis, autophagy, and specific cell signaling pathways. Moreover, immunodeficient mice
were engrafted with SUDHL2 cells and then treated with CPI-0610 for analysis of tumor burden.
We also analyzed the synergistic effect of CPI-0610 with histone deacetylase inhibitor suberoylanilide
hydroxamic acid.
Results::
The present study demonstrated that CPI-0610 displayed cell cytotoxicity by arresting
the G1 cell cycle and inducing endogenous and exogenous apoptotic pathways. Additionally,
CPI-0610 decreased BRD4 and c-Myc expressions and affected MAPK, JAK/STAT, and AKT signalling
pathways in human DLBCL cells. An in vivo experiment exhibited that CPI-0610 decreased
the primary tumour growth of the DLBCL xenograft model. Furthermore, the use of
CPI-0610 in combination with suberoylanilide hydroxamic acid exhibited a specific synergistic effect
in inducing apoptosis through the regulation of STAT3 and p38.
Conclusion::
Targeting BET may be an effective therapeutic strategy and potentiated by a combination
with histone deacetylase inhibition in DLBCL.
Publisher
Bentham Science Publishers Ltd.
Subject
Pharmacology,Molecular Medicine,Drug Discovery,Biochemistry,Organic Chemistry