TP-0903 inhibits neuroblastoma cell growth and enhances the sensitivity to conventional chemotherapy
Sanja Aveic1, Diana Corallo1, Elena Porcù2
1Pediatric Research Institute - Città della Speranza, Neuroblastoma Laboratory, Padua, Italy.
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.
Insights
The novel multi-kinase inhibitor TP-0903 effectively reduces high-risk neuroblastoma (NB) cell growth, proliferation, and migration. It also enhances the efficacy of conventional chemotherapy, supporting its potential for clinical use in NB treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- High-risk neuroblastoma (NB) presents a complex genomic profile and poor cure rates, necessitating novel therapeutic strategies.
- Existing treatments for NB often require aggressive approaches due to the tumor's intricate nature.
Purpose of the Study:
- To evaluate the efficacy of the novel multi-kinase inhibitor TP-0903 against neuroblastoma cells.
- To assess TP-0903's impact on NB cell growth, proliferation, motility, and its potential in combination therapies.
Main Methods:
- In vitro studies utilized NB cell lines with diverse molecular backgrounds.
- In vivo efficacy was assessed using the zebrafish experimental model.
- Assays included cytotoxicity, apoptosis, colony formation, neurosphere creation, migration, cell cycle, and intravasation analyses.
Main Results:
- TP-0903 demonstrated potent, irreversible cytotoxicity and induced caspase-dependent apoptosis in NB cells at sub-micromolar concentrations.
- The inhibitor impaired colony formation, neurosphere creation, and NB cell migration and cell cycle progression.
- TP-0903 significantly reduced NB cell intravasation both in vitro and in vivo.
- Remarkable efficacy was observed for TP-0903 as a mono-treatment and in combination with conventional chemotherapy drugs (ATRA, cisplatin, VP16).
Conclusions:
- The multi-kinase activity of TP-0903 targets multiple biological processes crucial for NB expansion.
- TP-0903 renders NB cells more susceptible to conventional chemotherapeutics.
- These findings support the further preclinical and clinical evaluation of TP-0903 for neuroblastoma treatment.
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