title: Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma: the role of survivin.
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.
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Denis
authors.initials: D
authors.lastname: Cominetti
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Doldi
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lopergolo
authors.affiliation: Peritoneal Surface Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Deraco
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gandellini
authors.affiliation: Karyopharm Therapeutics Inc., Newton, MA, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Friedlander
authors.affiliation: Karyopharm Therapeutics Inc., Newton, MA, USA.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Landesman
authors.affiliation: Karyopharm Therapeutics Inc., Newton, MA, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kauffman
authors.affiliation: Karyopharm Therapeutics Inc., Newton, MA, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Pennati
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D028884:Karyopherins / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D000077022:Survivin; D013844:Thiazoles / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000097606:Exportin 1 Protein
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006834:Hydrazines; D051034:Inhibitor of Apoptosis Proteins; D028884:Karyopherins; D009363:Neoplasm Proteins; D010069:Oxadiazoles; D018160:Receptors, Cytoplasmic and Nuclear; D000077022:Survivin; D013844:Thiazoles; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D000097606:Exportin 1 Protein; C107489:BIRC5 protein, human; C493957:Cdkn1a protein, mouse; C000603655:KPT-251; C586831:KPT-276; C585161:selinexor
keywords: SINE; XPO1/CRM1; diffuse malignant peritoneal mesothelioma; survivin