Identification of Cytotoxic Medication That Selectively Focus on Tumor Cells.

Frenzel A, Zirath H, Vita M, Albihn A, Henriksson MA. "PLoS One. 2011"

Expression of MYC is deregulated inside a wide range of human cancers, and it is normally associated with aggressive illness and poorly differentiated tumor cells. Identification of compounds with selectivity for cells overexpressing MYC would therefore be advantageous for that therapy of those tumors.

For this goal we used cell lines with conditional MYCN or c-MYC expression, to screen a library of eighty standard cytotoxic compounds for their ability to minimize tumor cell viability and/or development in a MYC dependent way.

We discovered that 25% from the researched compounds induced apoptosis and/or inhibited proliferation in a MYC-specific method. The activities of the majority of those had been improved both by c-MYC or MYCN over-expression.

Interestingly, these compounds were acting on unique mobile targets, including microtubules (paclitaxel, podophyllotoxin, vinblastine) and topoisomerases (10-hydroxycamptothecin, camptothecin, daunorubicin, doxorubicin, etoposide) also as DNA, RNA and protein synthesis and turnover (anisomycin, aphidicholin, gliotoxin, MG132, methotrexate, mitomycin C).

Our data show that MYC overexpression sensitizes cells to disruption of precise pathways and that in most cases c-MYC and MYCN overexpression have similar results within the responses to cytotoxic compounds.

Treatment from the cells with topoisomerase I inhibitors led to down-regulation of MYC protein levels, when doxorubicin and also the small molecule MYRA-A was located to disrupt MYC-Max interaction.

We conclude the MYC pathway is simply specific by a subset of standard cytotoxic medications at the moment made use of inside the clinic. Elucidating the mechanisms underlying their specificity in direction of MYC might be of value for optimizing remedy of tumors with MYC deregulation.

Our data also underscores that MYC is an desirable target for novel therapies and that mobile screenings of Compound Libraries is usually a strong tool for figuring out compounds with a desired biological activity.