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

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5 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 Jan 1

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Simvastatin
Hepatocellular Carcinoma
Cell Line
Caspase 9
Caspase 3
Pharmaceutical Preparations
Fluorescent Antibody Technique
Cyclooxygenase 2 Inhibitors
Cyclin D1
Bromodeoxyuridine
Caspases
N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
Flow Cytometry
Oxidoreductases
Western Blotting
Enzyme-Linked Immunosorbent Assay
Apoptosis

Keywords

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

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

@article{e988f3a2b7c24ca0bcfdba1bd875fc15,
title = "Synergistic effect of simvastatin plus NS398 on inhibition of proliferation and survival in hepatocellular carcinoma cell line",
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.",
keywords = "Combination drug therapy, Cyclooxygenase-2 inhibitor, Hepatocellular carcinoma, Simvastatin",
author = "Lee, {Sun Jae} and Hwang, {Ji Won} and Hyungshin Yim and Yim, {Hyung Joon} and Woo, {Sang Uk} and Suh, {Sang Jun} and Hyun, {Jong Jin} and Jung, {Sung Woo} and Koo, {Ja Seol} and Kim, {Ji Hoon} and Seo, {Yeon Seok} and Yeon, {Jong Eun} and Lee, {Sang Woo} and Byun, {Kwan Soo} and Soon-Ho Um",
year = "2014",
month = "1",
day = "1",
doi = "10.1111/jgh.12503",
language = "English",
volume = "29",
pages = "1299--1307",
journal = "Journal of Gastroenterology and Hepatology (Australia)",
issn = "0815-9319",
publisher = "Wiley-Blackwell",
number = "6",

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TY - JOUR

T1 - Synergistic effect of simvastatin plus NS398 on inhibition of proliferation and survival in hepatocellular carcinoma cell line

AU - Lee, Sun Jae

AU - Hwang, Ji Won

AU - Yim, Hyungshin

AU - Yim, Hyung Joon

AU - Woo, Sang Uk

AU - Suh, Sang Jun

AU - Hyun, Jong Jin

AU - Jung, Sung Woo

AU - Koo, Ja Seol

AU - Kim, Ji Hoon

AU - Seo, Yeon Seok

AU - Yeon, Jong Eun

AU - Lee, Sang Woo

AU - Byun, Kwan Soo

AU - Um, Soon-Ho

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - Combination drug therapy

KW - Cyclooxygenase-2 inhibitor

KW - Hepatocellular carcinoma

KW - Simvastatin

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U2 - 10.1111/jgh.12503

DO - 10.1111/jgh.12503

M3 - Article

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JF - Journal of Gastroenterology and Hepatology (Australia)

SN - 0815-9319

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