title: A systems biology approach to investigate the mechanism of action of trabectedin in a model of myelomonocytic leukemia.
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.
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Mannarino
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Paracchini
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Craparotta
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Romano
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Marchini
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.|Department of Bioscience, University of Milan, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Gatta
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Erba
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Clivio
authors.affiliation: Department of Biology, University of Padua, Padua, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Romualdi
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: D'Incalci
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Beltrame
authors.affiliation: Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
authors.forename: L
authors.identifier: 0000-0003-2237-0961
authors.initials: L
authors.lastname: Pattini
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D049490:Systems Biology / Q000379:methods; D000077606:Trabectedin / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000077606:Trabectedin