Abstract
We used small molecule screening to discover compounds and mechanisms for overcoming E6 oncogene-mediated drug resistance. Using high-throughput screening in isogenic cell lines, we identified compounds that potentiate doxorubicin's lethality in E6-expressing colon cancer cells. Such compounds included quaternary ammonium salts, protein synthesis inhibitors, 11-deoxyprostaglandins, and two additional classes of compounds-analogs of 1,3-bis(4-morpholinylmethyl)-2-imidazolidinethione (a thiourea) and acylated secondary amines that we named indoxins. Indoxins upregulated topoisomerase IIalpha, the target of doxorubicin, thereby increasing doxorubicin lethality. We developed a photolabeling strategy to identify targets of indoxin and discovered a nuclear actin-related protein complex as a candidate indoxin target.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alprostadil / analogs & derivatives
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Alprostadil / chemistry
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Alprostadil / pharmacology
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Survival
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Doxorubicin / pharmacology
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Drug Evaluation, Preclinical / methods*
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Drug Resistance, Neoplasm / drug effects*
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Ethylenethiourea / analogs & derivatives
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Ethylenethiourea / chemistry
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Ethylenethiourea / pharmacology
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Fluorescent Dyes
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Humans
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Oncogene Proteins, Viral / genetics
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Oncogene Proteins, Viral / metabolism*
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Organic Chemicals / chemistry
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Organic Chemicals / pharmacology
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Protein Synthesis Inhibitors / chemistry
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Protein Synthesis Inhibitors / pharmacology
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Quaternary Ammonium Compounds / chemistry
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Quaternary Ammonium Compounds / pharmacology
Substances
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Antineoplastic Agents
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Fluorescent Dyes
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Oncogene Proteins, Viral
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Organic Chemicals
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Protein Synthesis Inhibitors
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Quaternary Ammonium Compounds
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Ethylenethiourea
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Doxorubicin
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Alprostadil
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11-deoxyprostaglandin E1