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• W1492131844 abstract "// Michelandrea De Cesare 1, * , Denis Cominetti 1, * , Valentina Doldi 1 , Alessia Lopergolo 1 , Marcello Deraco 2 , Paolo Gandellini 1 , Sharon Friedlander 3 , Yosef Landesman 3 , Michael G. Kauffman 3 , Sharon Shacham 3 , Marzia Pennati 1, * , Nadia Zaffaroni 1, * 1 Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy 2 Peritoneal Surface Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy 3 Karyopharm Therapeutics Inc., Newton, MA, USA * These authors have contributed equally to this work Correspondence to: Nadia Zaffaroni, e-mail: nadia.zaffaroni@istitutotumori.mi.it Keywords: diffuse malignant peritoneal mesothelioma, SINE, survivin, XPO1/CRM1 Received: December 30, 2014      Accepted: April 06, 2015      Published: April 18, 2015 ABSTRACT Survivin, which is highly expressed and promotes cell survival in diffuse malignant peritoneal mesothelioma (DMPM), exclusively relies on exportin 1 (XPO1/CRM1) to be shuttled into the cytoplasm and perform its anti-apoptotic function. Here, we explored the efficacy of Selective Inhibitors of Nuclear Export (SINE), KPT-251, KPT-276 and the orally available, clinical stage KPT-330 (selinexor), in DMPM preclinical models. Exposure to SINE induced dose-dependent inhibition of cell growth, cell cycle arrest at G1-phase and caspase-dependent apoptosis, which were consequent to a decrease of XPO1/CRM1 protein levels and the concomitant nuclear accumulation of its cargo proteins p53 and CDKN1a. Cell exposure to SINE led to a time-dependent reduction of cytoplasmic survivin levels. In addition, after an initial accumulation, the nuclear protein abundance progressively decreased, as a consequence of an enhanced ubiquitination and proteasome-dependent degradation. SINE and the survivin inhibitor YM155 synergistically cooperated in reducing DMPM cell proliferation. Most importantly, orally administered SINE caused a significant anti-tumor effect in subcutaneous and orthotopic DMPM xenografts without appreciable toxicity. Overall, we have demonstrated a marked efficacy of SINE in DMPM preclinical models that may relay on the interference with survivin intracellular distribution and function. Our study suggests SINE-mediated XPO1/CRM1 inhibition as a novel therapeutic option for DMPM." @default.
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• W1492131844 date "2015-04-18" @default.
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• W1492131844 title "Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma: the role of survivin" @default.
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• W1492131844 doi "https://doi.org/10.18632/oncotarget.3761" @default.
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