PUBLICATION
TP-0903 inhibits neuroblastoma cell growth and enhances the sensitivity to conventional chemotherapy
- Authors
- Aveic, S., Corallo, D., Porcù, E., Pantile, M., Boso, D., Zanon, C., Viola, G., Sidarovich, V., Mariotto, E., Quattrone, A., Basso, G., Tonini, G.P.
- ID
- ZDB-PUB-171121-7
- Date
- 2017
- Source
- European Journal of Pharmacology 818: 435-448 (Journal)
- Registered Authors
- Aveic, Sanja, Corallo, Diana, Pantile, Marcella
- Keywords
- ATRA, TP-0903, drug combination, neuroblastoma, spheroids, zebrafish
- MeSH Terms
-
- Receptor Protein-Tyrosine Kinases/metabolism
- Cell Movement/drug effects
- Sulfonamides/pharmacology*
- Aurora Kinase A/metabolism
- Drug Synergism
- Cell Proliferation/drug effects
- DNA Damage
- Cell Cycle/drug effects
- Cell Survival/drug effects
- Antineoplastic Agents/pharmacology*
- Pyrimidines/pharmacology*
- Proto-Oncogene Proteins/metabolism
- Humans
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic/drug effects
- Neuroblastoma/pathology*
- PubMed
- 29154838 Full text @ Eur. J. Pharmacol.
Citation
Aveic, S., Corallo, D., Porcù, E., Pantile, M., Boso, D., Zanon, C., Viola, G., Sidarovich, V., Mariotto, E., Quattrone, A., Basso, G., Tonini, G.P. (2017) TP-0903 inhibits neuroblastoma cell growth and enhances the sensitivity to conventional chemotherapy. European Journal of Pharmacology. 818:435-448.
Abstract
Neuroblastoma (NB) is an embryonal tumor with low cure rate for patients classified as high-risk. This class of NB tumors shows a very complex genomic background and requires aggressive treatment strategies. In this work we evaluated the efficacy of the novel multi-kinase inhibitor TP-0903 in impairing NB cells' growth, proliferation and motility. In vitro studies were performed using cell lines with different molecular background, and in vivo studies were done using the zebrafish experimental model. Our results confirmed a strong cytotoxicity of TP-0903 already at the sub-micro molar concentrations. The observed cytotoxicity of TP-0903 was irreversible and the resulting apoptosis was caspase dependent. In addition, TP-0903 impaired colony formation and neurosphere creation. Depending on the molecular background of the selected NB cell lines, TP-0903 influenced either their capacity to migrate, to complete their cell cycle or both. Likewise, TP-0903 reduced NB cells intravasation in vitro and in vivo. Importantly, TP-0903 showed remarkable pharmacological efficacy not only as a mono-treatment, but also in combination with conventional chemotherapy drugs (ATRA, cisplatin, and VP16) in different types of NB cells. In conclusion, the multi-kinase activity of TP-0903 allowed the impairment of several biological processes required for expansion of NB cells, making them more vulnerable to the conventional chemotherapeutics. Altogether, our results support the eligibility of TP-0903 for further (pre)clinical assessments in NB.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping