Oncotarget

Research Papers:

In silico and in vitro identification of inhibitory activities of sorafenib on histone deacetylases in hepatocellular carcinoma cells

Tsang-Pai Liu, Yi-Han Hong and Pei-Ming Yang _

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Oncotarget. 2017; 8:86168-86180. https://doi.org/10.18632/oncotarget.21030

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Abstract

Tsang-Pai Liu1,2,3,4,5, Yi-Han Hong2 and Pei-Ming Yang1,6

1PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan

2Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan

3Mackay Junior College of Medicine, Nursing and Management, New Taipei City, Taiwan

4Department of Medicine, Mackay Medical College, New Taipei City, Taiwan

5Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan

6Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

Correspondence to:

Pei-Ming Yang, email: yangpm@tmu.edu.tw

Keywords: connectivity map (CMap), hepatocellular carcinoma (HCC), histone deacetylase (HDAC), polypharmacology, sorafenib

Received: May 07, 2017     Accepted: August 02, 2017     Published: September 16, 2017

ABSTRACT

Although sorafenib has been approved for treating hepatocellular carcinoma (HCC), clinical results are not satisfactory. Polypharmacology (one drug with multiple molecular targets) is viewed as an attractive strategy for identifying novel mechanisms of a drug and then rationally designing more-effective next-generation therapeutic agents. In this study, a polypharmacological study of sorafenib was performed by mining the next-generation Connectivity Map (CMap) database, CLUE (https://clue.io/). We found that sorafenib may act as a histone deacetylase (HDAC) inhibitor based on similar gene expression profiles. In vitro experimental analyses demonstrated that sorafenib indirectly inhibited HDAC activity in both sorafenib-sensitive and -resistant HCC cells. A cancer genomics analysis using the cBioPortal online tool showed the frequent upregulation of HDAC mRNAs. Furthermore, HCC patients with higher expressions of HDAC1 and HDAC2 had worse overall survival. Taken together, our study suggests that inhibition of HDAC by sorafenib may provide clinical benefits against HCC, and enhancement of HDAC-inhibitory activity of sorafenib may improve its therapeutic efficacy. In addition, our study also provides a novel strategy to study polypharmacology.


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