A systems biology approach to investigate the mechanism of action of trabectedin in a model of myelomonocytic leukemia

L. Mannarino, Lara Paracchini, I. Craparotta, M. Romano, Sergio Marchini, R. Gatta, Eugenio Erba, L. Clivio, C. Romualdi, M. D’Incalci, Luca Beltrame, L. Pattini

Research output: Contribution to journalArticle

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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.The Pharmacogenomics Journal advance online publication, 13 December 2016; doi:10.1038/tpj.2016.76.

Original languageEnglish
JournalPharmacogenomics Journal
DOIs
Publication statusAccepted/In press - Dec 13 2016

Fingerprint

trabectedin
Systems Biology
Leukemia
irinotecan
Topoisomerase I Inhibitors
Thioridazine
Regulon
Dopamine Antagonists
Gene Regulatory Networks
Pharmacogenetics
Gene Expression Profiling
Therapeutic Uses
Publications
Transcription Factors
Pharmacology
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

A systems biology approach to investigate the mechanism of action of trabectedin in a model of myelomonocytic leukemia. / Mannarino, L.; Paracchini, Lara; Craparotta, I.; Romano, M.; Marchini, Sergio; Gatta, R.; Erba, Eugenio; Clivio, L.; Romualdi, C.; D’Incalci, M.; Beltrame, Luca; Pattini, L.

In: Pharmacogenomics Journal, 13.12.2016.

Research output: Contribution to journalArticle

Mannarino, L. ; Paracchini, Lara ; Craparotta, I. ; Romano, M. ; Marchini, Sergio ; Gatta, R. ; Erba, Eugenio ; Clivio, L. ; Romualdi, C. ; D’Incalci, M. ; Beltrame, Luca ; Pattini, L. / A systems biology approach to investigate the mechanism of action of trabectedin in a model of myelomonocytic leukemia. In: Pharmacogenomics Journal. 2016.
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