TP-0903 inhibits neuroblastoma cell growth and enhances the sensitivity to conventional chemotherapy

Eur J Pharmacol. 2018 Jan 5:818:435-448. doi: 10.1016/j.ejphar.2017.11.016. Epub 2017 Nov 14.


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.

Keywords: ATRA; Drug combination; Neuroblastoma; Spheroids; TP-0903; Zebrafish.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Aurora Kinase A / metabolism
  • Axl Receptor Tyrosine Kinase
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • DNA Damage
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Neuroblastoma / pathology*
  • Proto-Oncogene Proteins / metabolism
  • Pyrimidines / pharmacology*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Sulfonamides / pharmacology*


  • Antineoplastic Agents
  • Proto-Oncogene Proteins
  • Pyrimidines
  • Sulfonamides
  • dubermatinib
  • Receptor Protein-Tyrosine Kinases
  • Aurora Kinase A
  • Axl Receptor Tyrosine Kinase
  • AXL protein, human