Abstract
Reactivation of mutant p53 in tumours is a promising strategy for cancer therapy. Here we characterise the novel p53 rescue compound P53R3 that restores sequence-specific DNA binding of the endogenously expressed p53(R175H) and p53(R273H) mutants in gel-shift assays. Overexpression of the paradigmatic p53 mutants p53(R175H), p53(R248W) and p53(R273H) in the p53 null glioma cell line LN-308 reveals that P53R3 induces p53-dependent antiproliferative effects with much higher specificity and over a wider range of concentrations than the previously described p53 rescue drug p53 reactivation and induction of massive apoptosis (PRIMA-1). Furthermore, P53R3 enhances recruitment of endogenous p53 to several target promoters in glioma cells bearing mutant (T98G) and wild-type (LNT-229) p53 and induces mRNA expression of numerous p53 target genes in a p53-dependent manner. Interestingly, P53R3 strongly enhances the mRNA, total protein and cell surface expression of the death receptor death receptor 5 (DR5) whereas CD95 and TNF receptor 1 levels are unaffected. Accordingly, P53R3 does not sensitise for CD95 ligand- or tumour necrosis factor alpha-induced cell death, but displays synergy with Apo2L.0 in 9 of 12 glioma cell lines. Both DR5 surface induction and synergy with Apo2L.0 are sensitive to siRNA-mediated downregulation of p53. Thus this new p53 rescue compound may open up novel perspectives for the treatment of cancers currently considered resistant to the therapeutic induction of apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects*
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Apoptosis / genetics
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Aza Compounds / pharmacology
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cell Survival / drug effects
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Cells, Cultured
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Dose-Response Relationship, Drug
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Electrophoretic Mobility Shift Assay
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Gene Expression Regulation, Neoplastic / drug effects*
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Glioma / drug therapy*
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Glioma / genetics
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Glioma / metabolism
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Glioma / pathology
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Humans
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Mutation
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Promoter Regions, Genetic / drug effects
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Quinazolines / pharmacology*
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Quinazolines / therapeutic use
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RNA Interference
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RNA, Messenger / metabolism
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RNA, Small Interfering / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
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TNF-Related Apoptosis-Inducing Ligand / metabolism*
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Transfection
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Tumor Suppressor Protein p53 / agonists*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Up-Regulation
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Valine / analogs & derivatives*
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Valine / pharmacology
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Valine / therapeutic use
Substances
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Antineoplastic Agents
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Aza Compounds
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Bridged Bicyclo Compounds, Heterocyclic
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P53R3 compound
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Quinazolines
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RNA, Messenger
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RNA, Small Interfering
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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TP53 protein, human
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Tumor Suppressor Protein p53
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2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one
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Valine