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.

C-MYC modulation induces responsiveness to paclitaxel in adrenocortical cancer cell lines

“…Some cytotoxic compounds were indentified, and currently used in oncology, able to reduce tumor cell viability and induce apoptosis in a C-MYC-dependent manner on a wide variety of cell lines (40). In the series of the drugs tested, paclitaxel, a microtubule target, revealed increased activity in cells overexpressing C-MYC.…”

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

“…97 MYC has a shorter half-life than BCL2 (;4 vs ;24 hours), and inhibiting translation or transcription is effective in treating Em-Myc lymphomas. 97,98 In fact, this may be one of the mechanisms by which conventional chemotherapy, such as doxorubicin, can decrease MYC protein levels, 99 and why it is effective in curing human BL. 100,101 The revision of the WHO classification coincides with a time when there are several targeted therapies that are approved by the Food and Drug Administration for other indications and could theoretically be prescribed off label to treat patients with HGBL-DH or DE-DLBCL.…”

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

“…Due to its key role in tumorigenesis, much recent research has been directed to finding ways to target c-MYC function (24)(25)(26)(27)(28)(29). Dominant-negative approaches targeting c-MYC function impair intestinal tumor formation, and c-Myc heterozygous mice show reduced tumor development in the Apc min/+ model (16,17).…”