title: Targeting the invasive phenotype of cisplatin-resistant non-small cell lung cancer cells by a novel histone deacetylase inhibitor.
abstract: Non-Small Cell Lung Cancer (NSCLC) remains an aggressive and fatal disease with low responsiveness to chemotherapy, frequent drug resistance development and metastatic behavior. Platinum-based therapy is the standard of care for NSCLC with limited benefits. Since epigenetic alterations have been implicated in the aggressive behavior of lung cancer, the purpose of the present study was to examine the capability of the pan-histone deacetylase inhibitor SAHA and of ST3595, a novel hydroxamate-based compound, to interfere with the proliferative and invasive potential of NSCLC cells. We used two NSCLC cell lines (H460 and A549) and the cisplatin-resistant variants (H460/Pt and A549/Pt), to mimic a frequent clinical condition. The resistant models exhibited increased invasive properties as compared to parental cells, features associated with a wide modulation of the level of angiogenesis- and invasion-related factors in the cell conditioned media. The levels of urokinase-type plasminogen activator, IL-8, and macrophage migration inhibitory factor were increased in the conditioned media from both H460/Pt and A549/Pt cells. SAHA and ST3595 induced a strong inhibition of cell invasive properties, which was more marked after ST3595 exposure. Both HDAC inhibitors up-regulated the metastasis suppressor KiSS1 at the mRNA level. Forced expression of KiSS1 significantly decreased the invasive capability of drug-resistant cells. ST3595 displayed an anti-metastatic effect in tumors associated with decreased of phosphorylation of Src. Our data indicate that HDAC inhibitors are effective in NSCLC cell systems. The ability of ST3595 to counteract the invasive potential of resistant cells through mechanisms involving KiSS1 is an interesting novel finding.
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Via Venezian 1/Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuco
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Via Venezian 1/Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cassinelli
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Via Venezian 1/Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Cossa
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Via Venezian 1/Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Gatti
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Via Venezian 1/Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Favini
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Via Venezian 1/Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Tortoreto
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Via Venezian 1/Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Denis
authors.initials: D
authors.lastname: Cominetti
authors.affiliation: Dipartimento di Scienze Veterinarie e Sanità Pubblica, Università degli Studi di Milano, Via Celoria 10, 20133 Milan, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Scanziani
authors.affiliation: Dipartimento di Scienze Veterinarie e Sanità Pubblica, Università degli Studi di Milano, Via Celoria 10, 20133 Milan, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Castiglioni
authors.affiliation: Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università di Milano, Via Celoria 2, 20133 Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Cincinelli
authors.affiliation: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina, Km. 30.400, 00040 Pomezia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Via Venezian 1/Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Via Venezian 1/Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Via Venezian 1/Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lanzi
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Via Venezian 1/Via Amadeo 42, 20133 Milan, Italy. Electronic address: paola.perego@istitutotumori.mi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Perego
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D059648:Kisspeptins / Q000187:drug effects; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D010641:Phenotype
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; C491407:Kiss1 protein, mouse; D059648:Kisspeptins; D002945:Cisplatin
keywords: Cisplatin; Drug resistance; Histone deacetylase inhibitor; Non-Small Cell Lung Cancer