MS275 as Class I HDAC inhibitor displayed therapeutic potential on malignant ascites by iTRAQ-based quantitative proteomic analysis

Li Du,Xiaohua Hou,Chang Liu,Zhuanglong Xiao,Wei Qian,Yuhu Song,Xiuqi Wei,Dongyuan Wang

doi:10.1186/s12876-022-02101-7

Abstract

BackgroundMalignant ascites is a manifestation of end stage events in a variety of cancers and is associated with significant morbidity. Epigenetic modulators play a key role in cancer initiation and progression, among which histone deacetylases (HDACs) are considered as one of the most important regulators for various cancer development, such as liver cancer, ovarian cancer, and pancreatic cancer et al. Thus, in this paper, we sought to explore the therapeutic effect of HDAC inhibitor on malignant ascites.MethodsIn this report, we tested the therapeutic effect of different isoform selective HDAC inhibitors (Class I HDACI MS275, Class IIa HDACI MC1568, pan-HDAC inhibitors SAHA) on malignant ascites in vitro and in vivo. We further used proteome analysis to find the potential mechanisms for malignant ascites therapy.ResultsAmong the different isoform-selective HDAC inhibitors, the class I selective HDACI, MS275, exhibited preferential inhibition on various ascites cells. MS275 could induce cell cycle arrest in G0/G1 phase and promote apoptosis on ascites cells. Through proteome analysis, we found MS275 could downregulate proteins related to cell cycle progression, such as CDK4, CDC20, CCND1; MS275 could upregulate pro-apoptosis proteins such as PAPR1, LMNB2 and AIFM1; in addition, MS275 could change the expression of tumorigenic proteins related to the specific malignant ascites bearing tumors, such as TSP1 and CDK4 for bladder cancer. We then confirmed that abemaciclib (CDK4/6 selective inhibitor) could inhibit the proliferation of ascites cells, and the combination of abemaciclib and MS275 had synergistic anti-tumor effect. Finally, we found that MS275 could in vivo inhibit malignant ascites progression (ascites volume: 2.9 ± 1.0 mL vs 7.5 ± 1.2 mL, p < 0.01), tumor growth, and prolong 66% of the life-span when compared with the untreated group.ConclusionThis present research revealed that the class I selective HDAC inhibitor, MS275, could effectively inhibit malignant ascites development and tumor growth via multiple pathways. These results indicated that HDACI could have great potential for clinical therapy of malignant ascites.

Highlights

Malignant ascites is a manifestation of end stage events in a variety of cancers and is associated with significant morbidity
Due to the complex sources of Malignant ascites (MA) and the limited therapeutic methods, in this paper we investigated the therapeutic effect of Histone deacetylases inhibitor (HDACI), the broadspectrum anticancer drug, on malignant ascites and further analysis the anti-tumor mechanism through proteome analysis
The HDACIs were dissolved in 1640 medium (10%FBS) containing 0.4% (v/v) dimethyl sulfoxide (DMSO), and the control group were treated with 0.4% (v/v) DMSO alone. 10 μL CCK8 reagent was added to 96-well plates and incubated for another 3 h

Summary

Introduction

Malignant ascites is a manifestation of end stage events in a variety of cancers and is associated with significant morbidity. Epigenetic modulators play a key role in cancer initiation and progression, among which histone deacetylases (HDACs) are considered as one of the most important regulators for various cancer development, such as liver cancer, ovarian cancer, and pancreatic cancer et al in this paper, we sought to explore the therapeutic effect of HDAC inhibitor on malignant ascites. MS275 (entinostat), the class I selective HDAC inhibitor, have been proved to be effective on various solid tumor (such as renal cancer, breast cancer, melanoma) and hematological malignancies in phase I and II clinical trials [12,13,14,15,16,17,18]

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