The small molecule SI113 synergizes with mitotic spindle poisons in arresting the growth of human glioblastoma multiforme

// Claudia Abbruzzese 1, * , Giada Catalogna 2, * , Enzo Gallo 3 , Simona di Martino 3 , Anna M. Mileo 4 , Mariantonia Carosi 3 , Vincenzo Dattilo 2 , Silvia Schenone 5 , Francesca Musumeci 5 , Patrizia Lavia 6 , Nicola Perrotti 2 , Rosario Amato 2 and Marco G. Paggi 1 1 Department of Research, Advanced Diagnostics and Technological Innovation, Unit of Cellular Networks and Therapeutic Targets, “Regina Elena” National Cancer Institute, IRCCS, Rome, Italy 2 Department of “Scienze della Salute”, University “Magna Graecia” of Catanzaro, Catanzaro, Italy 3 Department of Research, Advanced Diagnostics and Technological Innovation, Unit of Pathology, “Regina Elena” National Cancer Institute, IRCCS, Rome, Italy 4 Department of Research, Advanced Diagnostics and Technological Innovation, Unit of Tumor Immunology and Immunotherapy, “Regina Elena” National Cancer Institute, IRCCS, Rome, Italy 5 Department of Pharmacy, University of Genova, Genova, Italy 6 Institute of Molecular Biology and Pathology (IBPM), National Research Council of Italy (CNR), c/o University “La Sapienza”, Rome, Italy * These authors contributed equally to this work Correspondence to: Marco G. Paggi, email: marco.paggi@ifo.gov.it Rosario Amato, email: rosario.amato@unicz.it Keywords: glioblastoma multiforme; SI113; SGK1; vincristine; in vivo cancer therapy Received: August 09, 2017      Accepted: October 29, 2017      Published: November 18, 2017 ABSTRACT Glioblastoma multiforme (GBM) is the deadliest brain tumor. State-of-art GBM therapy often fails to ensure control of a disease characterized by high frequency of recurrences and progression. In search for novel therapeutic approaches, we assayed the effect of compounds from a cancer drug library on the ADF GBM cell line, establishing their elevated sensitivity to mitotic spindle poisons. Our previous work showed that the effectiveness of the spindle poison paclitaxel in inhibiting cancer cell growth was dependent on the expression of RANBP1, a regulatory target of the serine/threonine kinase SGK1. Recently, we developed the small molecule SI113 to inhibit SGK1 activity. Therefore, we explored the outcome of the association between SI113 and selected spindle poisons, finding that these drugs generated a synergistic cytotoxic effect in GBM cells, drastically reducing their viability and clonogenic capabilities in vitro , as well as inhibiting tumor growth in vivo . We also defined the molecular bases of such a synergistic effect. Because SI113 displays low systemic toxicity, yet strong activity in potentiating the effect of radiotherapy in GBM cells, we believe that this drug could be a strong candidate for clinical trials, with the aim to add it to the current GBM therapeutic approaches.