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Synergistic effect of simvastatin plus NS 398 on inhibition of proliferation and survival in hepatocellular carcinoma cell line
Author(s) -
Lee Sun Jae,
Hwang Ji Won,
Yim Hyungshin,
Yim Hyung Joon,
Woo Sang Uk,
Suh Sang Jun,
Hyun Jong Jin,
Jung Sung Woo,
Koo Ja Seol,
Kim Ji Hoon,
Seo Yeon Seok,
Yeon Jong Eun,
Lee Sang Woo,
Byun Kwan Soo,
Um Soon Ho
Publication year - 2014
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.12503
Subject(s) - simvastatin , medicine , apoptosis , pharmacology , cyclin d1 , cell growth , hepatocellular carcinoma , flow cytometry , cell culture , cell cycle , growth inhibition , immunofluorescence , microbiology and biotechnology , cancer research , immunology , chemistry , biology , antibody , biochemistry , cancer , genetics
Background and Aims NS 398, 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 NS 398 and simvastatin and its mechanism. Methods The H ep3 B and H uh‐7 cell lines were cultured. Cells were treated with simvastatin, NS 398, 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 NS 398 resulted in a greater effect on proliferation and apoptosis. In H ep3 B cells, co‐administration of the two drugs resulted in a greater decrease in procaspase 3 and B cl‐2 and an increase in cleaved caspase 9 than that noted with monotherapy. In H uh‐7 cells, co‐administration of the two drugs resulted in a greater decrease in procaspase 3 and cyclin D 1 and an increase in cleaved caspase 9. Expression of NF ‐ κB and A kt 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 NS 398. The effect was greater by co‐administration. Conclusions The co‐administration of NS 398 and simvastatin produced greater antiproliferative and proapoptotic effects against H ep3 B cells and H uh‐7 cells. Inhibition of the NF ‐ κB and A kt pathway and activation of caspase cascade, which are considered as the major mechanism of synergistic anticancer properties, were observed in both cell lines.