title: Identification of cytotoxic drugs that selectively target tumor cells with MYC overexpression.
abstract: Expression of MYC is deregulated in a wide range of human cancers, and is often associated with aggressive disease and poorly differentiated tumor cells. Identification of compounds with selectivity for cells overexpressing MYC would hence be beneficial for the treatment of these tumors. For this purpose we used cell lines with conditional MYCN or c-MYC expression, to screen a library of 80 conventional cytotoxic compounds for their ability to reduce tumor cell viability and/or growth in a MYC dependent way. We found that 25% of the studied compounds induced apoptosis and/or inhibited proliferation in a MYC-specific manner. The activities of the majority of these were enhanced both by c-MYC or MYCN over-expression. Interestingly, these compounds were acting on distinct cellular targets, including microtubules (paclitaxel, podophyllotoxin, vinblastine) and topoisomerases (10-hydroxycamptothecin, camptothecin, daunorubicin, doxorubicin, etoposide) as well as DNA, RNA and protein synthesis and turnover (anisomycin, aphidicholin, gliotoxin, MG132, methotrexate, mitomycin C). Our data indicate that MYC overexpression sensitizes cells to disruption of specific pathways and that in most cases c-MYC and MYCN overexpression have similar effects on the responses to cytotoxic compounds. Treatment of the cells with topoisomerase I inhibitors led to down-regulation of MYC protein levels, while doxorubicin and the small molecule MYRA-A was found to disrupt MYC-Max interaction. We conclude that the MYC pathway is only targeted by a subset of conventional cytotoxic drugs currently used in the clinic. Elucidating the mechanisms underlying their specificity towards MYC may be of importance for optimizing treatment of tumors with MYC deregulation. Our data also underscores that MYC is an attractive target for novel therapies and that cellular screenings of chemical libraries can be a powerful tool for identifying compounds with a desired biological activity.
authors: Department of Microbiology Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors: Anna
authors: A
authors: Frenzel
authors: Hanna
authors: H
authors: Zirath
authors: Marina
authors: M
authors: Vita
authors: Ami
authors: A
authors: Albihn
authors: Marie Arsenian
authors: MA
authors: Henriksson
mesh_terms: D000970:Antineoplastic Agents / Q000032:analysis* / Q000494:pharmacology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D020128:Inhibitory Concentration 50; D009447:Neuroblastoma / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004273:DNA, Neoplasm; C499330:MAX protein, human; D016271:Proto-Oncogene Proteins c-myc; D059004:Topoisomerase I Inhibitors; D004317:Doxorubicin; D004264:DNA Topoisomerases, Type I