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Effect of imatinib mesylate on neuroblastoma tumorigenesis and vascular endothelial growth factor expression
Kiichiro Beppu1, Jerry Jaboine, Melinda S Merchant
1Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Background:
Alternative treatment options are needed for advanced neuroblastoma patients because their prognosis remains poor after intensive chemotherapy. Neuroblastoma cells express platelet-derived growth factor (PDGF), stem cell factor (SCF), and vascular endothelial growth factor (VEGF) and their respective receptors, PDGFR, c-Kit, and Flk-1. We therefore evaluated the effects of imatinib mesylate (imatinib), a selective inhibitor of the tyrosine kinase activities of c-Kit and PDGFR, on the growth of neuroblastoma cells in vivo and in vitro.
Methods:
We tested seven human neuroblastoma cell lines for their sensitivity to imatinib. Cell viability was assessed by trypan blue dye exclusion. Apoptosis was evaluated by nuclear staining, flow cytometry, and western blotting. Protein assays included immunoprecipitation, western blotting, enzyme-linked immunosorbent assays, and immunohistochemistry. mRNA expression was assessed by northern blotting. We used a xenograft model in SCID mice (10 mice per group) to evaluate the effects of imatinib oral therapy (50 or 100 mg/kg every 12 hours for 14 days) on neuroblastoma tumor growth. All statistical tests were two-sided.
Results:
All seven neuroblastoma cell lines treated with imatinib displayed concentration-dependent decreases in cell viability, which coincided with an induction of apoptosis, and with ligand-stimulated phosphorylation of c-Kit and PDGFR. The imatinib concentrations that caused 50% inhibition of growth and 50% inhibition of ligand-induced phosphorylation of these receptors were 9-13 micro M and 0.1-0.5 microM, respectively. Expression of VEGF, but not phosphorylation of Flk-1, its receptor, was reduced in neuroblastoma cells treated with imatinib at 10 microM or higher. Mice treated with imatinib at 50 mg/kg or 100 mg/kg had statistically significantly smaller tumors than control mice treated with vehicle (mean tumor volume in mice treated with imatinib at 50 mg/kg = 1546 mm3, in control mice = 2954 mm3; difference = 1408 mm3, 95% confidence interval [CI] = 657 to 2159 mm3; P<.001; mean tumor volume in mice treated with imatinib at 100 mg/kg = 463 mm3; difference = 2491 mm3, 95% CI = 1740 to 3242 mm3; P<.001).
Conclusions:
Imatinib inhibited the growth of neuroblastoma cells in vitro and in vivo. This inhibition was associated with suppression of PDGFR and c-Kit phosphorylation and inhibition of VEGF expression.
Insights
Imatinib mesylate effectively inhibited neuroblastoma cell growth in vitro and in vivo by targeting platelet-derived growth factor receptor (PDGFR) and c-Kit phosphorylation, offering a potential new treatment for advanced neuroblastoma.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Advanced neuroblastoma patients have a poor prognosis despite intensive chemotherapy.
- Neuroblastoma cells express growth factors like PDGF, SCF, and VEGF, and their receptors (PDGFR, c-Kit, Flk-1).
- Imatinib mesylate is a tyrosine kinase inhibitor targeting c-Kit and PDGFR.
Purpose of the Study:
- To evaluate the efficacy of imatinib mesylate in inhibiting neuroblastoma cell growth.
- To investigate the molecular mechanisms underlying imatinib's effects on neuroblastoma cells in vitro and in vivo.
Main Methods:
- Tested imatinib sensitivity in seven human neuroblastoma cell lines.
- Assessed cell viability, apoptosis, protein phosphorylation (PDGFR, c-Kit, Flk-1), and mRNA expression.
- Utilized a neuroblastoma xenograft mouse model to evaluate imatinib's in vivo anti-tumor effects.
Main Results:
- Imatinib demonstrated dose-dependent inhibition of neuroblastoma cell viability and induced apoptosis.
- Imatinib suppressed ligand-stimulated phosphorylation of c-Kit and PDGFR.
- In vivo studies showed statistically significant reduction in tumor volume in mice treated with imatinib.
Conclusions:
- Imatinib mesylate effectively inhibits neuroblastoma cell growth both in vitro and in vivo.
- The anti-cancer effects are linked to the suppression of PDGFR and c-Kit phosphorylation and reduced VEGF expression.
