| A high-throughput screen with isogenic PTEN+/+ and PTEN-/- cells identifies CID1340132 as a novel compound that induces apoptosis in PTEN and PIK3CA mutant human cancer cells. | |
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MedLine Citation:
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PMID: 21335596 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The PTEN tumor suppressor gene is one of the most commonly mutated genes in human cancer. Because inactivation of PTEN is a somatic event, PTEN mutations represent an important genetic difference between cancer cells and normal cells and therefore a potential anticancer drug target. However, it remains a substantial challenge to identify compounds that target loss-of-function events such as mutations of tumor suppressors. In an effort to identify small molecules that preferentially kill cells with mutations of PTEN, the authors developed and implemented a high-throughput, paired cell-based screen composed of parental HCT116 cells and their PTEN gene-targeted derivatives. From 138 758 compounds tested, two hits were identified, and one, N'-[(1-benzyl-1H-indol-3-yl)methylene]benzenesulfonohydrazide (CID1340132), was further studied using a variety of cell-based models, including HCT116, MCF10A, and HEC1A cells with targeted deletion of either their PTEN or PIK3CA genes. Preferential killing of PTEN and PIK3CA mutant cells was accompanied by DNA damage, inhibition of DNA synthesis, and apoptosis. Taken together, these data validate a cell-based screening approach for identifying lead compounds that target cells with specific tumor suppressor gene mutations and describe a novel compound with preferential killing activity toward PTEN and PIK3CA mutant cells. |
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Authors:
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Hui-Fang Li; Adam Keeton; Michele Vitolo; Clinton Maddox; Lynn Rasmussen; Judith Hobrath; E Lucille White; Ben Ho Park; Gary A Piazza; Jung-Sik Kim; Todd Waldman |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-02-18 |
Journal Detail:
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Title: Journal of biomolecular screening Volume: 16 ISSN: 1552-454X ISO Abbreviation: J Biomol Screen Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-04-07 Completed Date: 2011-08-01 Revised Date: 2011-09-22 |
Medline Journal Info:
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Nlm Unique ID: 9612112 Medline TA: J Biomol Screen Country: United States |
Other Details:
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Languages: eng Pagination: 383-93 Citation Subset: IM |
Affiliation:
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Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC 20007, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology* Apoptosis / drug effects* Cell Line, Tumor Cell Proliferation / drug effects Cyclin D / metabolism Cyclin-Dependent Kinase Inhibitor p27 / metabolism DNA Damage / drug effects Drug Screening Assays, Antitumor HCT116 Cells High-Throughput Screening Assays* Humans Indoles / pharmacology* Mutation / genetics Neoplasms / genetics* PTEN Phosphohydrolase / genetics* Phosphatidylinositol 3-Kinases / genetics* Proto-Oncogene Proteins c-akt / metabolism Reproducibility of Results Sulfonamides / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA115699/CA/NCI NIH HHS; R01 CA115699-05/CA/NCI NIH HHS; R03 NS050857/NS/NINDS NIH HHS; R03 NS050857-01/NS/NINDS NIH HHS; U54 HG003917/HG/NHGRI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/CID1340132; 0/Cyclin D; 0/Indoles; 0/Sulfonamides; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.1.137/PIK3CA protein, human; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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