Preclinical assessment of histone deacetylase inhibitor quisinostat as a therapeutic agent against esophageal squamous cell carcinoma

Autor: Shu Zhou, Wenzhao Liu, Rongsheng Tong, Yuxuan Zhu, Lei Zhong, Lan Bai, Qian Peng, Lingyu Su, Xingmei Duan, Jin-ku Bao, Jianyou Shi
Rok vydání: 2018
Předmět:
0301 basic medicine
MAPK/ERK pathway
Cell cycle checkpoint
Esophageal Neoplasms
Cell Survival
medicine.drug_class
Pharmacology toxicology
Apoptosis
Histone Deacetylase 1
Mice
SCID
Hydroxamic Acids
Esophageal squamous cell carcinoma
Metastasis
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cell Movement
Cell Line
Tumor
Animals
Humans
Medicine
Pharmacology (medical)
neoplasms
Protein kinase B
PI3K/AKT/mTOR pathway
Cell Proliferation
Pharmacology
Drug candidate
business.industry
TOR Serine-Threonine Kinases
Histone deacetylase inhibitor
Quisinostat
Cell Cycle Checkpoints
medicine.disease
digestive system diseases
Tumor Burden
Histone Deacetylase Inhibitors
030104 developmental biology
Pharmaceutical Preparations
Oncology
chemistry
Head and Neck Neoplasms
030220 oncology & carcinogenesis
Cancer research
Esophageal Squamous Cell Carcinoma
Mitogen-Activated Protein Kinases
business
Proto-Oncogene Proteins c-akt
Zdroj: Investigational New Drugs. 37:616-624
ISSN: 1573-0646
0167-6997
Popis: Esophageal squamous cell carcinoma (ESCC) is one of the most serious life-threatening malignancies. Although chemotherapeutic targets and agents for ESCC have made much progress recently, the efficacy is still unsatisfactory. Therefore, there is still an unmet medical need for patients with ESCC. Here, we report the expression status of HDAC1 in human ESCC and matched paracancerous tissues, and the results indicated that HDAC1 was generally upregulated in ESCC specimens. Furthermore, we comprehensively assessed the anti-ESCC activity of a highly active HDAC1 inhibitor quisinostat. Quisinostat could effectively suppress cellular viability and proliferation of ESCC cells, as well as induce cell cycle arrest and apoptosis even at low treatment concentrations. The effectiveness was also observed in KYSE150 xenograft model when quisinostat was administered at tolerated doses (3 mg/kg and 10 mg/kg). Meanwhile, quisinostat also had the ability to suppress the migration and invasion (pivotal steps of tumor metastasis) of ESCC cells. Western blot analysis indicated that quisinostat exerted its anti-ESCC effects mainly through blockade of Akt/mTOR and MAPK/ERK signaling cascades. Overall, HDAC1 may serve as a potential therapeutic target for ESCC, and quisinostat deserves to be further assessed as a promising drug candidate for the treatment of ESCC.
Databáze: OpenAIRE
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