Novel combination of sorafenib and celecoxib provides synergistic anti-proliferative and pro-apoptotic effects in human liver cancer cells

PLoS One. 2013 Jun 12;8(6):e65569. doi: 10.1371/journal.pone.0065569. Print 2013.

Abstract

Molecular targeted therapy has shown promise as a treatment for advanced hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, recently received FDA approval for the treatment of advanced HCC. However, although sorafenib is well tolerated, concern for its safety has been expressed. Celecoxib (Celebrex®) is a selective cyclooxygenase-2 (COX-2) inhibitor which exhibits antitumor effects in human HCC cells. The present study examined the interaction between celecoxib and sorafenib in two human liver tumor cell lines HepG2 and Huh7. Our data showed that each inhibitor alone reduced cell growth and the combination of celecoxib with sorafenib synergistically inhibited cell growth and increased apoptosis. To better understand the molecular mechanisms underlying the synergistic antitumor activity of the combination, we investigated the expression profile of the combination-treated liver cancer cell lines using microarray analysis. Combination treatment significantly altered expression levels of 1,986 and 2,483 transcripts in HepG2 and Huh7 cells, respectively. Genes functionally involved in cell death, signal transduction and regulation of transcription were predominantly up-regulated, while genes implicated in metabolism, cell-cycle control and DNA replication and repair were mainly down-regulated upon treatment. However, combination-treated HCC cell lines displayed specificity in the expression and activity of crucial factors involved in hepatocarcinogenesis. The altered expression of some of these genes was confirmed by semi-quantitative and quantitative RT-PCR and by Western blotting. Many novel genes emerged from our transcriptomic analyses, and further functional analyses may determine whether these genes can serve as potential molecular targets for more effective anti-HCC strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Blotting, Western
  • Carcinoma, Hepatocellular / drug therapy*
  • Celecoxib
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • DNA Primers / genetics
  • Drug Synergism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • In Situ Nick-End Labeling
  • Liver Neoplasms / drug therapy*
  • Microarray Analysis
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Phenylurea Compounds / pharmacology*
  • Pyrazoles / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Sorafenib
  • Sulfonamides / pharmacology*

Substances

  • DNA Primers
  • Phenylurea Compounds
  • Pyrazoles
  • Sulfonamides
  • Niacinamide
  • Sorafenib
  • Celecoxib

Grants and funding

This work was supported in part by grants from the Italian “Ministero dell’Istruzione, dell’Università e della Ricerca (Ministry for Education, Universities and Research) – MIUR FIRB427 MERIT n.RBNE08YYBM to M.C. and G.M.; D.B. is the Head of the Core Genomic Facility at the CHUQ-Cancer Research Centre, supported by FRSQ-RR Cancer. All the genomic experiments and data analyses were performed at this facility; M.C. has also been supported in part by a grant to the CNR from the Italian Ministry of Economy and Finance for the Project FaReBio di Qualità. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.