2. Academic Validation
  3. The kinase inhibitor SI113 induces autophagy and synergizes with quinacrine in hindering the growth of human glioblastoma multiforme cells

The kinase inhibitor SI113 induces autophagy and synergizes with quinacrine in hindering the growth of human glioblastoma multiforme cells

  • J Exp Clin Cancer Res. 2019 May 17;38(1):202. doi: 10.1186/s13046-019-1212-1.
Silvia Matteoni 1,  Claudia Abbruzzese 1,  Paola Matarrese 2,  Gabriele De Luca 3,  Anna M Mileo 4,  Stefania Miccadei 4,  Silvia Schenone 5,  Francesca Musumeci 5,  Tobias L Haas 6,  Giovanni Sette 3,  Carmine M Carapella 7,  Rosario Amato 8,  Nicola Perrotti 8,  Michele Signore 9,  Marco G Paggi 10
Affiliations

Affiliations

  • 1 Section of Cellular Networks and Molecular Therapeutic Targets, Proteomics Unit, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
  • 2 Center for Gender-Specific Medicine, Oncology Unit, Istituto Superiore di Sanità, Rome, Italy.
  • 3 Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
  • 4 Tumor Immunology and Immunotherapy, IRCCS - Regina Elena National Cancer Institute, Rome, Italy.
  • 5 Department of Pharmacy, University of Genova, Genoa, Italy.
  • 6 Department of General Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.
  • 7 Division of Neurosurgery, IRCCS - Regina Elena National Cancer Institute, Rome, Italy.
  • 8 Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
  • 9 RPPA Unit, Proteomics Area, Core Facilities, Istituto Superiore di Sanità, Viale Regina Elena 299, 00162, Rome, Italy. michele.signore@iss.it.
  • 10 Section of Cellular Networks and Molecular Therapeutic Targets, Proteomics Unit, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy. marco.paggi@ifo.gov.it.
PMID: 31101126 DOI: 10.1186/s13046-019-1212-1
Abstract

Background: Glioblastoma multiforme (GBM), due to its location, aggressiveness, heterogeneity and infiltrative growth, is characterized by an exceptionally dismal clinical outcome. The small molecule SI113, recently identified as a SGK1 Inhibitor, has proven to be effective in restraining GBM growth in vitro and in vivo, showing also encouraging results when employed in combination with other antineoplastic drugs or radiotherapy. Our aim was to explore the pharmacological features of SI113 in GBM cells in order to elucidate the pivotal molecular pathways affected by the drug. Such knowledge would be of invaluable help in conceiving a rational offensive toward GBM.

Methods: We employed GBM cell lines, either established or primary (neurospheres), and used a Reverse-Phase Protein Arrays (RPPA) platform to assess the effect of SI113 upon 114 protein factors whose post-translational modifications are associated with activation or repression of specific signal transduction cascades.

Results: SI113 strongly affected the PI3K/mTOR pathway, evoking a pro-survival autophagic response in neurospheres. These results suggested the use of SI113 coupled, for maximum efficiency, with Autophagy inhibitors. Indeed, the association of SI113 with an Autophagy Inhibitor, the antimalarial drug quinacrine, induced a strong synergistic effect in inhibiting GBM growth properties in all the cells tested, including neurospheres.

Conclusions: RPPA clearly identified the molecular pathways influenced by SI113 in GBM cells, highlighting their vulnerability when the drug was administered in association with Autophagy inhibitors, providing a strong molecular rationale for testing SI113 in clinical trials in associative GBM therapy.

Keywords

Autophagy; Glioblastoma multiforme; Quinacrine; RPPA; SI113.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-117357
    98.02%, SGK1抑制剂
    SGK
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