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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

 Ki Cheong Park  ;  Jun Hyeok Heo  ;  Jeong Yong Jeon  ;  Hye Ji Choi  ;  A Ra Jo  ;  Seung Won Kim  ;  Ho Jeong Kwon  ;  Sung Joon Hong  ;  Kyung Seok Han 
 BMC CANCER, Vol.15 : 19, 2015 
Journal Title
Issue Date
Acetylation ; Animals ; Antineoplastic Agents/therapeutic use* ; Apoptosis/drug effects* ; Blotting, Western/methods ; Carcinoma, Renal Cell/drug therapy* ; Carcinoma, Renal Cell/enzymology ; Carcinoma, Renal Cell/pathology ; Caspases/metabolism ; Cell Fractionation/methods ; Cytochromes c/metabolism* ; Histone Deacetylase Inhibitors/therapeutic use* ; Histones/metabolism ; Humans ; Hydroxamic Acids/therapeutic use* ; I-kappa B Proteins/metabolism ; In Situ Nick-End Labeling ; Kidney Neoplasms/drug therapy* ; Kidney Neoplasms/enzymology ; Kidney Neoplasms/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondria/enzymology ; Naphthalenes/therapeutic use* ; Neoplasm Transplantation ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Tumor Cells, Cultured ; bcl-2-Associated X Protein/metabolism
HNHA ; Histone deacetylase (HDAC) inhibitor ; Renal cell carcinoma (RCC) ; Cytochrome c ; Apoptosis
BACKGROUND: 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.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Urology (비뇨의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Others (기타) > 1. Journal Papers
Yonsei Authors
Kim, Seung Won(김승원) ORCID logo https://orcid.org/0000-0002-1692-1192
Park, Ki Cheong(박기청) ORCID logo https://orcid.org/0000-0002-3435-3985
Han, Kyung Seok(한경석)
Hong, Sung Joon(홍성준) ORCID logo https://orcid.org/0000-0001-9869-065X
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