Synergistic effect of simvastatin plus NS398 on inhibition of proliferation and survival in hepatocellular carcinoma cell line

Sun Jae Lee, Ji Won Hwang, Hyungshin Yim, Hyung Joon Yim, Sang Uk Woo, Sang Jun Suh, Jong Jin Hyun, Sung Woo Jung, Ja Seol Koo, Ji Hoon Kim, Yeon Seok Seo, Jong Eun Yeon, Sang Woo Lee, Kwan Soo Byun, Soon Ho Um

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background and Aims: NS398, a selective cyclooxygenase-2 inhibitor, and simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, both exert an anticancer effect on hepatocellular carcinoma cells, but the effect of co-administration of the two drugs remains unknown. We aimed to investigate the synergistic in vitro anticancer effect of co-administration of NS398 and simvastatin and its mechanism. Methods: The Hep3B and Huh-7 cell lines were cultured. Cells were treated with simvastatin, NS398, or a combination. 5-bromo-2'-deoxyuridine ELISA assay, flow cytometry, Western blot analyses, and immunofluorescence assay were performed. Results: In both cell lines, co-administration of simvastatin and NS398 resulted in a greater effect on proliferation and apoptosis. In Hep3B cells, co-administration of the two drugs resulted in a greater decrease in procaspase 3 and Bcl-2 and an increase in cleaved caspase 9 than that noted with monotherapy. In Huh-7 cells, co-administration of the two drugs resulted in a greater decrease in procaspase 3 and cyclin D1 and an increase in cleaved caspase 9. Expression of NF-κB and Akt were also decreased to a greater extent when the two drugs were co-administered in both cell lines. Immunofluorescence assay showed suppression of the nuclear localization of NF-κB by simvastatin or NS398. The effect was greater by co-administration. Conclusions: The co-administration of NS398 and simvastatin produced greater antiproliferative and proapoptotic effects against Hep3B cells and Huh-7 cells. Inhibition of the NF-κB and Akt pathway and activation of caspase cascade, which are considered as the major mechanism of synergistic anticancer properties, were observed in both cell lines.

Original languageEnglish
Pages (from-to)1299-1307
Number of pages9
JournalJournal of Gastroenterology and Hepatology (Australia)
Volume29
Issue number6
DOIs
Publication statusPublished - 2014 Jun

Keywords

  • Combination drug therapy
  • Cyclooxygenase-2 inhibitor
  • Hepatocellular carcinoma
  • Simvastatin

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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