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We reported previously that<jats:styled-content style=\"fixed-case\">ZOL<\/jats:styled-content>delayed both the growth and pain progression of bone metastases from hepatocellular carcinoma. The present study was designed to evaluate the effects of<jats:styled-content style=\"fixed-case\">ZOL<\/jats:styled-content>on hepatoma cell lines and the molecular mechanisms of such effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cell viability assay, scratch assay, immunohistochemistry,<jats:styled-content style=\"fixed-case\">W<\/jats:styled-content>estern blotting, and flow cytometry analysis were performed using<jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>uh7 and<jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>ep<jats:styled-content style=\"fixed-case\">G<\/jats:styled-content>2 cells treated with and without<jats:styled-content style=\"fixed-case\">ZOL<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">ZOL<\/jats:styled-content>reduced cell growth in a dose\u2010dependent manner and prevented cell migration when used at a concentration exceeding 10\u2009\u03bcM. Immunohistochemistry showed that the inhibitory effects of<jats:styled-content style=\"fixed-case\">ZOL<\/jats:styled-content>on hepatoma cell progression was not due to the suppression of<jats:styled-content style=\"fixed-case\">R<\/jats:styled-content>as and<jats:styled-content style=\"fixed-case\">RhoA<\/jats:styled-content>expression but due to inhibition of their translocation from the cytosol to the cell membrane, which terminates mevalonate pathway. Immunoblotting and flow cytometry showed that<jats:styled-content style=\"fixed-case\">ZOL<\/jats:styled-content>inhibited the mitogen\u2010activated protein kinase pathway (MAPK) and induced apoptosis of hepatoma cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results indicated that<jats:styled-content style=\"fixed-case\">ZOL<\/jats:styled-content>prevented cell growth and metastasis based on direct antitumor effects in hepatoma cells. The use of<jats:styled-content style=\"fixed-case\">ZOL<\/jats:styled-content>could not only suppress the progression to bone metastatic lesions but also prevented growth of primary hepatocellular carcinoma.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jgh.12715","type":"journal-article","created":{"date-parts":[[2014,8,28]],"date-time":"2014-08-28T12:57:13Z","timestamp":1409230633000},"page":"619-627","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["The effects of bisphosphonate zoledronic acid in hepatocellular carcinoma, depending on mevalonate pathway"],"prefix":"10.1111","volume":"30","author":[{"given":"Yohji","family":"Honda","sequence":"first","affiliation":[{"name":"Department of Medicine and Molecular Science Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoichi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Medicine 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