title: Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma.
abstract: Malignant mesothelioma, a very aggressive tumor associated to asbestos exposure, is expected to increase in incidence, and unfortunately, no curative modality exists. Reactivation of p53 is a new attractive antitumoral strategy. p53 is rarely mutated in mesothelioma, but it is inactivated in most tumors by the lack of p14(ARF). Here, we evaluated the feasibility of this approach in pleural mesothelioma by testing RITA and nutlin-3, two molecules able to restore p53 function through a different mechanism, on a panel of mesothelioma cell lines representing the epithelioid (NCI-H28, NCI-H2452, IST-MES 2), biphasic (MSTO-211H), and sarcomatoid (NCI-H2052) histotypes compared with the normal mesothelial HMC-hTERT. RITA triggered robust caspase-dependent apoptosis specifically in epithelioid and biphasic mesothelioma cell lines, both through wild-type and mutant p53, concomitant to p21 downregulation. Conversely, nutlin-3 induced a p21-dependent growth arrest, rather than apoptosis, and was slightly toxic on HMC-hTERT.   Interestingly, we identified a previously undetected point mutation of p53 (p.Arg249Ser) in IST-MES 2, and showed that RITA is also able to reactivate this p53 mutant protein and its apoptotic function. RITA reduced tumor growth in a MSTO-211H-derived xenograft model of mesothelioma and synergized with cisplatin, which is the mainstay of treatment for this tumor. Our data indicate that reactivation of p53 and concomitant p21 downregulation effectively induce cell death in mesothelioma, a tumor characterized by a high intrinsic resistance to apoptosis. Altogether, our findings provide the preclinical framework supporting the use of p53-reactivating agents alone, or in combination regimens, to improve the outcome of patients with mesothelioma.
authors.affiliation: Oncology Research Center of Mercogliano (CROM); Istituto Nazionale Per Lo Studio E La Cura Dei Tumori "Fondazione Giovanni Pascale"; IRCCS; Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Di Marzo
authors.affiliation: Oncology Research Center of Mercogliano (CROM); Istituto Nazionale Per Lo Studio E La Cura Dei Tumori "Fondazione Giovanni Pascale"; IRCCS; Italy.
authors.forename: Iris Maria
authors.initials: IM
authors.lastname: Forte
authors.affiliation: Department of Medicine, Surgery and Neuroscience; University of Siena; Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine; Center for Biotechnology; College of Science and Technology; Temple University; Philadelphia, PA USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Indovina
authors.affiliation: Experimental Pharmacology Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS; Naples, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Di Gennaro
authors.affiliation: Department of Medicine, Surgery and Neuroscience; University of Siena; Siena, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Rizzo
authors.affiliation: Department of Medicine, Surgery and Neuroscience; University of Siena; Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Giorgi
authors.affiliation: Department of Medicine, Surgery and Neuroscience; University of Siena; Siena, Italy; National Cancer Research Centre; Istituto Tumori "Giovanni Paolo II"; Bari, Italy.
authors.forename: Eliseo
authors.initials: E
authors.lastname: Mattioli
authors.affiliation: Oncology Research Center of Mercogliano (CROM); Istituto Nazionale Per Lo Studio E La Cura Dei Tumori "Fondazione Giovanni Pascale"; IRCCS; Italy; Department of Medicine, Surgery and Neuroscience; University of Siena; Siena, Italy.
authors.forename: Carmelina Antonella
authors.initials: CA
authors.lastname: Iannuzzi
authors.affiliation: Oncology Research Center of Mercogliano (CROM); Istituto Nazionale Per Lo Studio E La Cura Dei Tumori "Fondazione Giovanni Pascale"; IRCCS; Italy; Experimental Pharmacology Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS; Naples, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Budillon
authors.affiliation: Oncology Research Center of Mercogliano (CROM); Istituto Nazionale Per Lo Studio E La Cura Dei Tumori "Fondazione Giovanni Pascale"; IRCCS; Italy; Department of Medicine, Surgery and Neuroscience; University of Siena; Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine; Center for Biotechnology; College of Science and Technology; Temple University; Philadelphia, PA USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.affiliation: Oncology Research Center of Mercogliano (CROM); Istituto Nazionale Per Lo Studio E La Cura Dei Tumori "Fondazione Giovanni Pascale"; IRCCS; Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pentimalli
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D005663:Furans / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D010997:Pleural Neoplasms / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D007093:Imidazoles; C118989:NSC 652287; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D020741:rho GTP-Binding Proteins; D002945:Cisplatin
keywords: RITA; TP53mutations; apoptosis; mesothelioma; nutlin-3; p21