Effect of imatinib mesylate on neuroblastoma tumorigenesis and vascular endothelial growth factor expression

Kiichiro Beppu, Jerry Jaboine, Melinda S. Merchant, Crystal L. Mackall, Carol J. Thiele

Research output: Contribution to journalArticle

Abstract

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 μM and 0.1-0.5 μM, respectively. Expression of VEGF, but not phosphorylation of Flk-1, its receptor, was reduced in neuroblastoma cells treated with imatinib at 10 μM 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; P3 ; difference = 2491 mm3, 95% CI = 1740 to 3242 mm3 ; P

Original languageEnglish (US)
Pages (from-to)46-55
Number of pages10
JournalJournal of the National Cancer Institute
Volume96
Issue number1
StatePublished - Jan 7 2004
Externally publishedYes

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Neuroblastoma
Vascular Endothelial Growth Factor A
Carcinogenesis
Phosphorylation
Cell Survival
Growth
Western Blotting
Confidence Intervals
Proto-Oncogene Proteins c-kit
Apoptosis
Ligands
Imatinib Mesylate
Cell Line
Stem Cell Factor
SCID Mice
Trypan Blue
Platelet-Derived Growth Factor
Tumor Burden
Immunoprecipitation
Heterografts

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Beppu, K., Jaboine, J., Merchant, M. S., Mackall, C. L., & Thiele, C. J. (2004). Effect of imatinib mesylate on neuroblastoma tumorigenesis and vascular endothelial growth factor expression. Journal of the National Cancer Institute, 96(1), 46-55.

Effect of imatinib mesylate on neuroblastoma tumorigenesis and vascular endothelial growth factor expression. / Beppu, Kiichiro; Jaboine, Jerry; Merchant, Melinda S.; Mackall, Crystal L.; Thiele, Carol J.

In: Journal of the National Cancer Institute, Vol. 96, No. 1, 07.01.2004, p. 46-55.

Research output: Contribution to journalArticle

Beppu, K, Jaboine, J, Merchant, MS, Mackall, CL & Thiele, CJ 2004, 'Effect of imatinib mesylate on neuroblastoma tumorigenesis and vascular endothelial growth factor expression', Journal of the National Cancer Institute, vol. 96, no. 1, pp. 46-55.
Beppu, Kiichiro ; Jaboine, Jerry ; Merchant, Melinda S. ; Mackall, Crystal L. ; Thiele, Carol J. / Effect of imatinib mesylate on neuroblastoma tumorigenesis and vascular endothelial growth factor expression. In: Journal of the National Cancer Institute. 2004 ; Vol. 96, No. 1. pp. 46-55.
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