In silico and in vitro identification of inhibitory activities of sorafenib on histone deacetylases in hepatocellular carcinoma cells
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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
Pei-Ming Yang, email: [email protected]
Keywords: connectivity map (CMap), hepatocellular carcinoma (HCC), histone deacetylase (HDAC), polypharmacology, sorafenib
Received: May 07, 2017 Accepted: August 02, 2017 Published: September 16, 2017
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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