Summary
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.
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Funding
This work was supported by the National Natural Science Foundation of China (81702286 and 81300882), the Fundamental Research Funds of Science & Technology Department of Sichuan Province (2017YSKY0001), and the Special Foundation for Young Scientists of Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital (2016QN11).
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L Zhong and S Zhou contributed equally to this article.
Conception and design: L Zhong, S Zhou, LY Su, and Q Peng;
Development of methodology: L Zhong, S Zhou, and RS Tong;
Acquisition of data: L Zhong, S Zhou, and JY Shi;
Analysis and interpretation of data: L Zhong, RS Tong, and Q Peng;
Technical and material supports: YX Zhu, L Bai, XM Duan, WZ Liu, and JK Bao; Writing and review of the manuscript: L Zhong, S Zhou, LY Su, and Q Peng;
Study supervision: RS Tong, LY Su, and Q Peng.
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All procedures performed in studies involving animals were in accordance with the ethical standards of the Animal Care and Use Committee of Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital (Chengdu, Sichuan, China).
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Zhong, L., Zhou, S., Tong, R. et al. Preclinical assessment of histone deacetylase inhibitor quisinostat as a therapeutic agent against esophageal squamous cell carcinoma. Invest New Drugs 37, 616–624 (2019). https://doi.org/10.1007/s10637-018-0651-4
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DOI: https://doi.org/10.1007/s10637-018-0651-4