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

Tobias Longin Haas, Giovanni Sette, Silvia Matteoni, Claudia Abbruzzese, Paola Matarrese, Gabriele De Luca, Anna M. Mileo, Stefania Miccadei, Silvia Schenone, Francesca Musumeci, Carmine M. Carapella, Rosario Amato, Nicola Perrotti, Michele Signore, Marco G. Paggi

Risultato della ricerca: Contributo in rivistaArticolo in rivista

16 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)202-215
Numero di pagine14
RivistaJOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
Volume38
DOI
Stato di pubblicazionePubblicato - 2019

Keywords

  • Autophagy
  • Glioblastoma multiforme
  • Quinacrine
  • RPPA
  • SI113

Fingerprint

Entra nei temi di ricerca di 'The kinase inhibitor SI113 induces autophagy and synergizes with quinacrine in hindering the growth of human glioblastoma multiforme cells'. Insieme formano una fingerprint unica.

Cita questo