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Plos One : Combinatorial Treatment of Dna and Chromatin- Modifying Drugs Cause Cell Death in Human and Canine Osteosarcoma Cell Lines, Volume 7

By Cinti, Caterina

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Book Id: WPLBN0003935256
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos One : Combinatorial Treatment of Dna and Chromatin- Modifying Drugs Cause Cell Death in Human and Canine Osteosarcoma Cell Lines, Volume 7  
Author: Cinti, Caterina
Volume: Volume 7
Language: English
Subject: Journals, Science, Medical Science
Collections: Periodicals: Journal and Magazine Collection
Historic
Publication Date:
Publisher: Plos

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Cinti, C. (n.d.). Plos One : Combinatorial Treatment of Dna and Chromatin- Modifying Drugs Cause Cell Death in Human and Canine Osteosarcoma Cell Lines, Volume 7. Retrieved from http://netlibrary.net/


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Description : Downregulation of microRNAs (miRNAs) at the 14q32 locus stabilizes the expression of cMYC, thus significantly contributing to osteosarcoma (OS) pathobiology. Here, we show that downregulation of 14q32 miRNAs is epigenetically regulated. The predicted promoter regions of miRNA clusters at 14q32 locus showed no recurrent patterns of differential methylation, but Saos2 cells showed elevated histone deacetylase (HDAC) activity. Treatment with 4-phenylbutyrate increased acetylation of histones associated with 14q32 miRNAs, but interestingly, robust restoration of 14q32 miRNA expression, attenuation of cMYC expression, and induction of apoptosis required concomitant treatment with 5-Azacytidine, an inhibitor of DNA methylation. These events were associated with genome-wide gene expression changes including induction of proapoptotic genes and downregulation of cell cycle genes. Comparable effects were achieved in human and canine OS cells using the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA/Vorinostat) and the DNA methylation inhibitor Zebularine (Zeb), with significantly more pronounced cytotoxicity in cells whose molecular phenotypes were indicative of aggressive biological behavior. These results suggested that the combination of these chromatin-modifying drugs may be a useful adjuvant in the treatment of rapidly progressive OS.

 

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