Abstract
This study was designed to investigate the mode of action of trabectedin in myelomonocytic leukemia cells by applying systems biology approaches to mine gene expression profiling data and pharmacological assessment of the cellular effects. Significant enrichment was found in regulons of target genes inferred for specific transcription factors, among which MAFB was the most upregulated after treatment and was central in the transcriptional network likely to be relevant for the specific therapeutic effects of trabectedin against myelomonocytic cells. Using the Connectivity Map, similarity among transcriptional signatures elicited by treatment with different compounds was investigated, showing a high degree of similarity between transcriptional signatures of trabectedin and those of the topoisomerase I inhibitor, irinotecan, and an anti-dopaminergic antagonist, thioridazine. The study highlights the potential importance of systems biology approaches to generate new hypotheses that are experimentally testable to define the specificity of the mechanism of action of drugs.
Highlights
Trabectedin (ET-743) is a DNA minor-groove binding agent originally isolated from the Caribbean tunicate Ecteinascidia turbinata and recently obtained by chemical synthesis.[1]
MATERIALS AND METHODS Drugs Trabectedin was supplied by PharmaMar (Colmenar Viejo, Madrid, Spain) and was stocked in dimethyl sulfoxide at a concentration of 1 mM and stored at − 20 °C. 5-azacytidine, thioridazine and SN-38 were purchased from Sigma (St Louis, MO, USA)
In the present study, we show that trabectedin is very effective in inhibiting cell proliferation and inducing apoptosis in MV-4-11 cells
Summary
Trabectedin (ET-743) is a DNA minor-groove binding agent originally isolated from the Caribbean tunicate Ecteinascidia turbinata and recently obtained by chemical synthesis.[1].
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