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The novel histone deacetylase inhibitor, N-hydroxy-7-(2-naphthylthio) hepatonomide, exhibits potent antitumor activity due to cytochrome-c-release-mediated apoptosis in renal cell carcinoma cells

DC FieldValueLanguage
dc.contributor.author한경석-
dc.contributor.author홍성준-
dc.contributor.author박기청-
dc.contributor.author김승원-
dc.date.accessioned2016-02-04T11:01:12Z-
dc.date.available2016-02-04T11:01:12Z-
dc.date.issued2015-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/139486-
dc.description.abstractBACKGROUND: Epigenetic modifications play a critical role in the regulation of all DNA-based processes, such as transcription, repair, and replication. Inappropriate histone modifications can result in dysregulation of cell growth, leading to neoplastic transformation and cell death. Renal tumors have been shown to have a higher global methylation percentage and reduced histone acetylation. Preclinical models have revealed that histone gene modifiers and epigenetic alterations play important roles in renal cell carcinoma (RCC) tumorigenesis. Recently, a novel HDAC inhibitor, N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), has been introduced as an example of a new class of anti-cancer agents. The anti-cancer activity of HNHA and the underlying mechanisms of action remain to be clarified. METHODS: The MTS assay using a panel of RCC cells was used to evaluate the anti-proliferative effects of HNHA. The established HDAC inhibitors, SAHA and TSA, were used for comparison. Western blotting analysis was performed to investigate the acetylation of histone H3 and the expression of apoptotic markers in vitro and in vivo. Subcellular fractionation was performed to evaluate expression of Bax and cytochrome c in the cytosol and mitochondria, and also translocation of cytochrome c from the cytoplasm to the nucleus. A confocal microscopic evaluation was performed to confirm inhibition of cell proliferation, induction of apoptosis, and the nuclear translocation of cytochrome c in RCC cells. RESULTS: In this study, we investigated the apoptosis-inducing activity of HNHA in cultured kidney cancer cells. Apoptosis in the HNHA-treated group was induced significantly, with marked caspase activation and Bcl-2 suppression in RCC cells in vitro and in vivo. HNHA treatment caused cytochrome c release from mitochondria, which was mediated by increased Bax expression and caspase activation. HNHA also induced nuclear translocation of cytochrome c, suggesting that HNHA can induce caspase-independent nuclear apoptosis in RCC cells. An in vivo study showed that HNHA had greater anti-tumor and pro-apoptotic effects on RCC xenografts than the established HDAC inhibitors. CONCLUSIONS: HNHA has more potent anti-tumor activity than established HDAC inhibitors. Its activities are mediated by caspase-dependent and cytochrome-c-mediated apoptosis in RCC cells. These results suggest that HNHA may offer a new therapeutic approach to RCC.-
dc.description.statementOfResponsibilityopen-
dc.formatapplication/pdf-
dc.relation.isPartOfBMC CANCER-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHAcetylation-
dc.subject.MESHAnimals-
dc.subject.MESHAntineoplastic Agents/therapeutic use*-
dc.subject.MESHApoptosis/drug effects*-
dc.subject.MESHBlotting, Western/methods-
dc.subject.MESHCarcinoma, Renal Cell/drug therapy*-
dc.subject.MESHCarcinoma, Renal Cell/enzymology-
dc.subject.MESHCarcinoma, Renal Cell/pathology-
dc.subject.MESHCaspases/metabolism-
dc.subject.MESHCell Fractionation/methods-
dc.subject.MESHCytochromes c/metabolism*-
dc.subject.MESHHistone Deacetylase Inhibitors/therapeutic use*-
dc.subject.MESHHistones/metabolism-
dc.subject.MESHHumans-
dc.subject.MESHHydroxamic Acids/therapeutic use*-
dc.subject.MESHI-kappa B Proteins/metabolism-
dc.subject.MESHIn Situ Nick-End Labeling-
dc.subject.MESHKidney Neoplasms/drug therapy*-
dc.subject.MESHKidney Neoplasms/enzymology-
dc.subject.MESHKidney Neoplasms/pathology-
dc.subject.MESHMice-
dc.subject.MESHMice, Inbred BALB C-
dc.subject.MESHMice, Nude-
dc.subject.MESHMitochondria/enzymology-
dc.subject.MESHNaphthalenes/therapeutic use*-
dc.subject.MESHNeoplasm Transplantation-
dc.subject.MESHProto-Oncogene Proteins c-bcl-2/metabolism-
dc.subject.MESHTumor Cells, Cultured-
dc.subject.MESHbcl-2-Associated X Protein/metabolism-
dc.titleThe novel histone deacetylase inhibitor, N-hydroxy-7-(2-naphthylthio) hepatonomide, exhibits potent antitumor activity due to cytochrome-c-release-mediated apoptosis in renal cell carcinoma cells-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Urology (비뇨기과학)-
dc.contributor.googleauthorKi Cheong Park-
dc.contributor.googleauthorJun Hyeok Heo-
dc.contributor.googleauthorJeong Yong Jeon-
dc.contributor.googleauthorHye Ji Choi-
dc.contributor.googleauthorA Ra Jo-
dc.contributor.googleauthorSeung Won Kim-
dc.contributor.googleauthorHo Jeong Kwon-
dc.contributor.googleauthorSung Joon Hong-
dc.contributor.googleauthorKyung Seok Han-
dc.identifier.doi10.1186/s12885-014-1003-1-
dc.admin.authorfalse-
dc.admin.mappingfalse-
dc.contributor.localIdA04264-
dc.contributor.localIdA04402-
dc.relation.journalcodeJ00351-
dc.identifier.eissn1471-2407-
dc.identifier.pmid25613585-
dc.subject.keywordHNHA-
dc.subject.keywordHistone deacetylase (HDAC) inhibitor-
dc.subject.keywordRenal cell carcinoma (RCC)-
dc.subject.keywordCytochrome c-
dc.subject.keywordApoptosis-
dc.contributor.alternativeNameHan, Kyung Seok-
dc.contributor.alternativeNameHong, Sung Joon-
dc.contributor.affiliatedAuthorHan, Kyung Seok-
dc.contributor.affiliatedAuthorHong, Sung Joon-
dc.rights.accessRightsfree-
dc.citation.volume15-
dc.citation.startPage19-
dc.identifier.bibliographicCitationBMC CANCER, Vol.15 : 19, 2015-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Urology (비뇨의학교실) > 1. Journal Papers

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