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

Tsang Pai Liu, Yi Han Hong, Pei Ming Yang

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)86168-86180
Number of pages13
JournalOncotarget
Volume8
Issue number49
DOIs
Publication statusPublished - Oct 17 2017

Keywords

  • Connectivity map (CMap)
  • Hepatocellular carcinoma (HCC)
  • Histone deacetylase (HDAC)
  • Polypharmacology
  • Sorafenib

ASJC Scopus subject areas

  • Oncology

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