Imatinib Mesylate Inhibits Platelet-Derived Growth Factor Receptor Phosphorylation of Melanoma Cells but Does Not Affect Tumorigenicity in Vivo

Eric C. McGary, Amir Onn, Lisa Mills, Amy Heimberger, Omar Eton, Gary W. Thomas, Mikhail Shtivelband, Menashe Bar-Eli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Platelet-derived growth factor (PDGF) and its cognate receptor are widely expressed on melanomas. Coexpression of the growth factor and receptor suggests their role in autocrine or paracrine growth mechanisms. Imatinib mesylate was previously reported to have specific activity in inhibiting select tyrosine kinase receptors, including PDGF and c-Kit. Melanoma cells express abundant levels of the PDGF receptor (PDGFR). Nevertheless, c-Kit expression is progressively lost as the cells take on a more highly metastatic phenotype. To investigate the potential of imatinib mesylate as a therapy for melanoma, we studied its effect on the growth of melanoma cells using an in vivo mouse model. Melanoma cells with high malignant potential (PDGFR-positive, c-Kit-negative) or low malignant potential (PDGFR-positive, c-Kit-positive) were injected subcutaneously into athymic nude mice. Mice were treated with imatinib mesylate (100 mg/kg three times weekly) or with phosphate-buffered saline for 4 to 6 wk. PDGFR-α and -β were expressed on all melanoma cell lines tested. The level of PDGFR expression correlated with the metastatic potential of the melanoma cells: higher levels of PDGFR-α were expressed on cells with higher metastatic potential, and higher levels of PDGFR-β were expressed on cells with lower metastatic potential. There was no significant difference in tumor size between treated and control mice. Immunohistochemical studies demonstrated inhibition of PDGFR phosphorylation on the tumors from mice treated with imatinib mesylate but not from control mice, suggesting that the receptors were functional and that the concentration of drug used was appropriate. Our data demonstrated that imatinib mesylate blocked both PDGFR-α and PDGFR-β in vivo. It did not, however, affect the growth of melanoma cells expressing PDGFR, regardless of whether the cells expressed c-Kit.

Original languageEnglish (US)
Pages (from-to)400-405
Number of pages6
JournalJournal of Investigative Dermatology
Volume122
Issue number2
DOIs
StatePublished - Feb 2004
Externally publishedYes

Keywords

  • Autocrine
  • Gleevec
  • Nude mice
  • Paracrine
  • STI571

ASJC Scopus subject areas

  • Dermatology
  • Molecular Biology
  • Biochemistry
  • Cell Biology

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