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

• Published in: BMC gastroenterology 2022-01, Vol.22 (1), p.29-29, Article 29
• Main Authors: Du, Li, Wang, Dongyuan, Wei, Xiuqi, Liu, Chang, Xiao, Zhuanglong, Qian, Wei, Song, Yuhu, Hou, Xiaohua
• Format: Article
• Language: English
• Subjects: Analysis; Angiogenesis; Apoptosis; Ascites; Ascites - drug therapy; Ascites cells; Bladder cancer; Cancer; CDK4; Cell cycle; Cell cycle arrest; Cell Line, Tumor; Cell proliferation; Colorectal cancer; Cyclin-dependent kinase 4; Diagnosis; Epigenetic inheritance; Epigenetics; Experiments; G1 phase; Gastroenterology; Health aspects; Histone deacetylase; Histone deacetylase inhibitor; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Histone Deacetylases; Histones; Humans; Laboratory animals; Liver cancer; Malignant ascites; Measurement; Melanoma; Morbidity; MS275; Ovarian cancer; Pancreatic cancer; Peptides; Proteins; Proteomes; Proteomic; Proteomics; Survival analysis; Thermodynamic processes; Tumors
• ISSN: 1471-230X; 1471-230X
• DOI: 10.1186/s12876-022-02101-7

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. Thus, in this paper, we sought to explore the therapeutic effect of HDAC inhibitor on malignant ascites. In 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. Among 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