title: The impact of arsenic trioxide and all-trans retinoic acid on p53 R273H-codon mutant glioblastoma.
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-p53(R273H) cells generated more rapid neurosphere growth than U87-p53(wt) but inhibition of neurosphere proliferation was seen with both ATO and ATRA. U87-p53(R273H) 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-p53(wt) and U87-p53(R273H) cells was reduced with ATO and ATRA in a dose-dependent manner. Elevated pERK1/2 and p53 expression was seen in U87-p53(R273H) 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.
authors.affiliation: Department of Neurosurgery, University of Utah, 175 North Medical Dr. East, Salt Lake City, UT, 84132, USA, Michael.Karsy@hsc.utah.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Karsy
authors.forename: Ladislau
authors.initials: L
authors.lastname: Albert
authors.forename: Raj
authors.initials: R
authors.lastname: Murali
authors.forename: Meena
authors.initials: M
authors.lastname: Jhanwar-Uniyal
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003062:Codon; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D016158:Genes, p53; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000473:pathology; D010087:Oxides / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D003062:Codon; D010087:Oxides; D014212:Tretinoin; D048049:Extracellular Signal-Regulated MAP Kinases; D000077237:Arsenic Trioxide