title: Mass spectrometric/bioinformatic identification of a protein subset that characterizes the cellular activity of anticancer peptides.
abstract: The preclinical study of the mechanism of action of anticancer small molecules is challenging due to the complexity of cancer biology and the fragmentary nature of available data. With the aim of identifying a protein subset characterizing the cellular activity of anticancer peptides, we used differential mass spectrometry to identify proteomic changes induced by two peptides, LR and [d-Gln(4)]LR, that inhibit cell growth and compared them with the changes induced by a known drug, pemetrexed, targeting the same enzyme, thymidylate synthase. The quantification of the proteome of an ovarian cancer cell model treated with LR yielded a differentially expressed protein data set with respect to untreated cells. This core set was expanded by bioinformatic data interpretation, the biologically relevant proteins were selected, and their differential expression was validated on three cis-platinum sensitive and resistant ovarian cancer cell lines. Via clustering of the protein network features, a broader view of the peptides' cellular activity was obtained. Differences from the mechanism of action of pemetrexed were inferred from different modulation of the selected proteins. The protein subset identification represents a method of general applicability to characterize the cellular activity of preclinical compounds and a tool for monitoring the cellular activity of novel drug candidates.
authors.affiliation: C.I.G.S., University of Modena and Reggio Emilia , Via G. Campi 213/A, Modena 41125, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Genovese
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gualandi
authors.forename: Laura
authors.initials: L
authors.lastname: Taddia
authors.forename: Gaetano
authors.initials: G
authors.lastname: Marverti
authors.forename: Silvia
authors.initials: S
authors.lastname: Pirondi
authors.forename: Chiara
authors.initials: C
authors.lastname: Marraccini
authors.forename: Paul
authors.initials: P
authors.lastname: Perco
authors.forename: Michela
authors.initials: M
authors.lastname: Pelà
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Amoroso
authors.forename: Franca
authors.initials: F
authors.lastname: Esposito
authors.forename: Andrea
authors.initials: A
authors.lastname: Martello
authors.forename: Glauco
authors.initials: G
authors.lastname: Ponterini
authors.forename: Domenico
authors.initials: D
authors.lastname: D'Arca
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Costi
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor / Q000187:drug effects; D019295:Computational Biology / Q000379:methods; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068437:Pemetrexed; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011506:Proteins / Q000032:analysis / Q000378:metabolism*; D015203:Reproducibility of Results; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D005971:Glutamates; D010455:Peptides; D011506:Proteins; D000068437:Pemetrexed; D006147:Guanine; D005492:Folic Acid; D013940:Thymidylate Synthase
keywords: anticancer drugs; bioinformatics; drug targets; folate pathway; human thymidylate synthase peptidic inhibitors; label-free quantification; ovarian cancer; pemetrexed