A high-content screening of anticancer compounds suggests the multiple tyrosine kinase inhibitor ponatinib for repurposing in neuroblastoma therapy

Viktoryia Sidarovich, Marilena De Mariano, Sanja Aveic, Michael Pancher, Valentina Adami, Pamela Gatto, Silvia Pizzini, Luigi Pasini, Michela Croce, Federica Parodi, Flora Cimmino, Marianna Avitabile, Laura Emionite, Michele Cilli, Silvano Ferrini, Aldo Pagano, Mario Capasso, Alessandro Quattrone, Gian Paolo Tonini, Luca Longo

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Novel druggable targets have been discovered in neuroblastoma (NB), paving the way for more effective treatments. However, children with high-risk NB still show high mortality rates prompting for a search of novel therapeutic options. Here, we aimed at repurposing FDA-approved drugs for NB treatment by performing a high-content screening of a 349 anticancer compounds library. In the primary screening, we employed three NB cell lines, grown as three-dimensional (3D) multicellular spheroids, which were treated with 10 μmol/L of the library compounds for 72 hours. The viability of 3D spheroids was evaluated using a high-content imaging approach, resulting in a primary hit list of 193 compounds. We selected 60 FDA-approved molecules and prioritized drugs with multi-target activity, discarding those already in use for NB treatment or enrolled in NB clinical trials. Hence, 20 drugs were further tested for their efficacy in inhibiting NB cell viability, both in two-dimensional and 3D models. Dose-response curves were then supplemented with the data on side effects, therapeutic index, and molecular targets, suggesting two multiple tyrosine kinase inhibitors, ponatinib and axitinib, as promising candidates for repositioning in NB. Indeed, both drugs showed induction of cell-cycle block and apoptosis, as well as inhibition of colony formation. However, only ponatinib consistently affected migration and inhibited invasion of NB cells. Finally, ponatinib also proved effective inhibition of tumor growth in orthotopic NB mice, providing the rationale for its repurposing in NB therapy.

Original languageEnglish
Pages (from-to)1405-1415
Number of pages11
JournalMolecular Cancer Therapeutics
Volume17
Issue number7
DOIs
Publication statusPublished - Jul 1 2018

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Neuroblastoma
Protein-Tyrosine Kinases
Therapeutics
Pharmaceutical Preparations
Libraries
ponatinib
Cellular Spheroids
Therapeutic Uses
Cell Survival
Cell Cycle
Clinical Trials
Apoptosis
Cell Line
Mortality

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A high-content screening of anticancer compounds suggests the multiple tyrosine kinase inhibitor ponatinib for repurposing in neuroblastoma therapy. / Sidarovich, Viktoryia; De Mariano, Marilena; Aveic, Sanja; Pancher, Michael; Adami, Valentina; Gatto, Pamela; Pizzini, Silvia; Pasini, Luigi; Croce, Michela; Parodi, Federica; Cimmino, Flora; Avitabile, Marianna; Emionite, Laura; Cilli, Michele; Ferrini, Silvano; Pagano, Aldo; Capasso, Mario; Quattrone, Alessandro; Tonini, Gian Paolo; Longo, Luca.

In: Molecular Cancer Therapeutics, Vol. 17, No. 7, 01.07.2018, p. 1405-1415.

Research output: Contribution to journalArticle

Sidarovich, V, De Mariano, M, Aveic, S, Pancher, M, Adami, V, Gatto, P, Pizzini, S, Pasini, L, Croce, M, Parodi, F, Cimmino, F, Avitabile, M, Emionite, L, Cilli, M, Ferrini, S, Pagano, A, Capasso, M, Quattrone, A, Tonini, GP & Longo, L 2018, 'A high-content screening of anticancer compounds suggests the multiple tyrosine kinase inhibitor ponatinib for repurposing in neuroblastoma therapy', Molecular Cancer Therapeutics, vol. 17, no. 7, pp. 1405-1415. https://doi.org/10.1158/1535-7163.MCT-17-0841
Sidarovich, Viktoryia ; De Mariano, Marilena ; Aveic, Sanja ; Pancher, Michael ; Adami, Valentina ; Gatto, Pamela ; Pizzini, Silvia ; Pasini, Luigi ; Croce, Michela ; Parodi, Federica ; Cimmino, Flora ; Avitabile, Marianna ; Emionite, Laura ; Cilli, Michele ; Ferrini, Silvano ; Pagano, Aldo ; Capasso, Mario ; Quattrone, Alessandro ; Tonini, Gian Paolo ; Longo, Luca. / A high-content screening of anticancer compounds suggests the multiple tyrosine kinase inhibitor ponatinib for repurposing in neuroblastoma therapy. In: Molecular Cancer Therapeutics. 2018 ; Vol. 17, No. 7. pp. 1405-1415.
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AU - Adami, Valentina

AU - Gatto, Pamela

AU - Pizzini, Silvia

AU - Pasini, Luigi

AU - Croce, Michela

AU - Parodi, Federica

AU - Cimmino, Flora

AU - Avitabile, Marianna

AU - Emionite, Laura

AU - Cilli, Michele

AU - Ferrini, Silvano

AU - Pagano, Aldo

AU - Capasso, Mario

AU - Quattrone, Alessandro

AU - Tonini, Gian Paolo

AU - Longo, Luca

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