Abstract
In tumors that retain wild-type p53, its tumor-suppressor function is often impaired as a result of the deregulation of HDM-2, which binds to p53 and targets it for proteasomal degradation. We have screened a chemical library and identified a small molecule named RITA (reactivation of p53 and induction of tumor cell apoptosis), which bound to p53 and induced its accumulation in tumor cells. RITA prevented p53-HDM-2 interaction in vitro and in vivo and affected p53 interaction with several negative regulators. RITA induced expression of p53 target genes and massive apoptosis in various tumor cells lines expressing wild-type p53. RITA suppressed the growth of human fibroblasts and lymphoblasts only upon oncogene expression and showed substantial p53-dependent antitumor effect in vivo. RITA may serve as a lead compound for the development of an anticancer drug that targets tumors with wild-type p53.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / metabolism*
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Apoptosis / drug effects
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DNA Primers
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Drug Screening Assays, Antitumor
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Enzyme-Linked Immunosorbent Assay
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Female
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Fibroblasts / drug effects
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Flow Cytometry
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Furans / chemistry
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Furans / metabolism
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Furans / pharmacology*
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Gene Expression Regulation / drug effects*
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Humans
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Immunoblotting
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Immunoprecipitation
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Lymphocytes / drug effects
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Mice
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Nuclear Proteins / metabolism*
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Plasmids / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-mdm2
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / antagonists & inhibitors
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Antineoplastic Agents
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DNA Primers
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Furans
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NSC 652287
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Nuclear Proteins
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2