Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma: the role of survivin
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Michelandrea De Cesare1,*, Denis Cominetti1,*, Valentina Doldi1, Alessia Lopergolo1, Marcello Deraco2, Paolo Gandellini1, Sharon Friedlander3, Yosef Landesman3, Michael G. Kauffman3, Sharon Shacham3, Marzia Pennati1,*, Nadia Zaffaroni1,*
1Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
2Peritoneal Surface Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
3Karyopharm Therapeutics Inc., Newton, MA, USA
*These authors have contributed equally to this work
Nadia Zaffaroni, e-mail: email@example.com
Keywords: diffuse malignant peritoneal mesothelioma, SINE, survivin, XPO1/CRM1
Received: December 30, 2014 Accepted: April 06, 2015 Published: April 18, 2015
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.
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