The small molecule SI113 synergizes with mitotic spindle poisons in arresting the growth of human glioblastoma multiforme
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Claudia Abbruzzese1,*, Giada Catalogna2,*, Enzo Gallo3, Simona di Martino3, Anna M. Mileo4, Mariantonia Carosi3, Vincenzo Dattilo2, Silvia Schenone5, Francesca Musumeci5, Patrizia Lavia6, Nicola Perrotti2, Rosario Amato2 and Marco G. Paggi1
1Department of Research, Advanced Diagnostics and Technological Innovation, Unit of Cellular Networks and Therapeutic Targets, “Regina Elena” National Cancer Institute, IRCCS, Rome, Italy
2Department of “Scienze della Salute”, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
3Department of Research, Advanced Diagnostics and Technological Innovation, Unit of Pathology, “Regina Elena” National Cancer Institute, IRCCS, Rome, Italy
4Department of Research, Advanced Diagnostics and Technological Innovation, Unit of Tumor Immunology and Immunotherapy, “Regina Elena” National Cancer Institute, IRCCS, Rome, Italy
5Department of Pharmacy, University of Genova, Genova, Italy
6Institute 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
Marco G. Paggi, email: firstname.lastname@example.org
Rosario Amato, email: email@example.com
Keywords: glioblastoma multiforme; SI113; SGK1; vincristine; in vivo cancer therapy
Received: August 09, 2017 Accepted: October 29, 2017 Published: November 18, 2017
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.
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