Using small molecules to overcome drug resistance induced by a viral oncogene.
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.
Smukste
Inese
I
Department of Biological Sciences and Department of Chemistry, Columbia University, Fairchild Center, MC 2406, 1212 Amsterdam Avenue, New York, New York 10027, USA.
Bhalala
Oneil
O
Persico
Marco
M
Stockwell
Brent R
BR
D000527:Alprostadil / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004317:Doxorubicin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005031:Ethylenethiourea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D005456:Fluorescent Dyes; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D009930:Organic Chemicals / Q000737:chemistry / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D009856:Oncogene Proteins, Viral; D009930:Organic Chemicals; D011500:Protein Synthesis Inhibitors; D000644:Quaternary Ammonium Compounds; D005031:Ethylenethiourea; D004317:Doxorubicin; D000527:Alprostadil; C034008:11-deoxyprostaglandin E1