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 language | English |
|---|---|
| Pages (from-to) | 1405-1415 |
| Number of pages | 11 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 17 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Jul 1 2018 |
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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 journal › Article
}
TY - JOUR
T1 - A high-content screening of anticancer compounds suggests the multiple tyrosine kinase inhibitor ponatinib for repurposing in neuroblastoma therapy
AU - Sidarovich, Viktoryia
AU - De Mariano, Marilena
AU - Aveic, Sanja
AU - Pancher, Michael
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
PY - 2018/7/1
Y1 - 2018/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85045926808&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045926808&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-17-0841
DO - 10.1158/1535-7163.MCT-17-0841
M3 - Article
AN - SCOPUS:85045926808
VL - 17
SP - 1405
EP - 1415
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 7
ER -