Document Detail


Combination treatment of renal cell carcinoma with belinostat and 5-fluorouracil: A role for oxidative stress-induced DNA damage and HSP90-regulated thymidine synthase.
MedLine Citation:
PMID:  25433307     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
PURPOSE: Despite the availability of several therapeutic options, renal cell carcinoma (RCC) is associated with poor clinical outcomes. Therefore, we investigated whether the combination of 5-fluoruracil (5-FU) with the histone deacetylase inhibitor (HDACI) belinostat would exert a synergistic effect on RCC cells in vitro and in vivo.
MATERIALS AND METHODS: We used SN12C cells treated with 5-FU and/or belinostat, both in vitro and in xenograft experiments in vivo. Cell viability and death mechanisms were assessed by MTS assay and Western blotting. To investigate the role of reactive oxygen species (ROS), we used 2,7A-dichlorodihydrofluorescin diacetate (H2DCF-DA), ROS scavengers, and the reduction/oxidation-sensitive green fluorescent protein 2 (roGFP2) construct.
RESULTS: Belinostat potentiated the anti-cancer effect of 5-FU, and synergistically induced apoptosis by activating caspases and increasing the sub-G1 cell population. The effects of ROS-mediated DNA damage included reduced expression of thioredoxin and elevation in the levels of thioredoxin-binding protein-2 (TBP-2), phosphorylated H2AX (γ-H2AX), and acetylated H3 (Ac-H3). Furthermore, belinostat attenuated the 5-FU-mediated induction of thymidylate synthase (TS) via hyper-acetylation of heat shock protein 90 (HSP90). Similarly, co-administration of 5-FU with belinostat reduced tumor volume and weight, and increased the level of γ-H2AX and Ac-H3 in the SN12C xenograft model.
CONCLUSIONS: In combination with 5-FU, the targeted inhibitor of HDAC synergistically inhibits renal cancer cell growth by blockade of TS induction and induction of ROS-mediated DNA damage in vitro and in vivo. Our results suggest that combined treatment with belinostat and 5-FU represents a promising new approach against renal cancer.
Authors:
Mi Joung Kim; Jee Suk Lee; Sang Eun Park; Hye-Jin Yi; In Gab Jeong; Jong Soon Kang; Jieun Yun; Joo-Yong Lee; Seonggu Ro; Jung Shin Lee; Eun Kyung Choi; Jung Jin Hwang; Choung-Soo Kim
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-11-26
Journal Detail:
Title:  The Journal of urology     Volume:  -     ISSN:  1527-3792     ISO Abbreviation:  J. Urol.     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-11-29     Completed Date:  -     Revised Date:  2014-11-30    
Medline Journal Info:
Nlm Unique ID:  0376374     Medline TA:  J Urol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
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