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Tumor Biology
Published in: Tumor Biology 5/2014

01-05-2014 | Research Article

The impact of arsenic trioxide and all-trans retinoic acid on p53 R273H-codon mutant glioblastoma

Authors: Michael Karsy, Ladislau Albert, Raj Murali, Meena Jhanwar-Uniyal

Published in: Tumor Biology | Issue 5/2014

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Abstract

Glioblastoma (GBM) is the most common primary brain tumor in adults and demonstrates a 1-year median survival time. Codon-specific hotspot mutations of p53 result in constitutively active mutant p53, which promotes aberrant proliferation, anti-apoptosis, and cell cycle checkpoint failure in GBM. Recently identified CD133+ cancer stem cell populations (CSC) within GBM also confer therapeutic resistance. We studied targeted therapy in a codon-specific p53 mutant (R273H) created by site-directed mutagenesis in U87MG. The effects of arsenic trioxide (ATO, 1 μM) and all-trans retinoic acid (ATRA, 10 μM), possible targeted treatments of CSCs, were investigated in U87MG neurospheres. The results showed that U87-p53R273H cells generated more rapid neurosphere growth than U87-p53wt but inhibition of neurosphere proliferation was seen with both ATO and ATRA. U87-p53R273H neurospheres showed resistance to differentiation into glial cells and neuronal cells with ATO and ATRA exposure. ATO was able to generate apoptosis at high doses and proliferation of U87-p53wt and U87-p53R273H cells was reduced with ATO and ATRA in a dose-dependent manner. Elevated pERK1/2 and p53 expression was seen in U87-p53R273H neurospheres, which could be reduced with ATO and ATRA treatment. Additionally, differential responses in pERK1/2 were seen with ATO treatment in neurospheres and non-neurosphere cells. In conclusion, codon-specific mutant p53 conferred a more aggressive phenotype to our CSC model. However, ATO and ATRA could potently suppress CSC properties in vitro and may support further clinical investigation of these agents.
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Metadata
Title
The impact of arsenic trioxide and all-trans retinoic acid on p53 R273H-codon mutant glioblastoma
Authors
Michael Karsy
Ladislau Albert
Raj Murali
Meena Jhanwar-Uniyal
Publication date
01-05-2014
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 5/2014
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-013-1601-6

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