Topical Treatment with Inhibitors of the Phosphatidylinositol 3′-Kinase/Akt and Raf/Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Pathways Reduces Melanoma Development in Severe Combined Immunodeficient Mice

Barbara Bedogni, Melony S. O'Neill, Scott M. Welford, Donna M. Bouley, Amato J. Giaccia, Nicholas C. Denko, Marianne Broome Powell

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

Topical treatment with inhibitors of the phosphatidylinositol 3′-kinase/ Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways inhibited the growth of TPras transgenic melanomas in severe combined immunodeficient mice, blocked invasive behavior, and reduced angiogenesis. The inhibitor Ly294002, which is specific for phosphatidylinositol 3′-kinase, effectively reduced melanoma cell growth both in vitro and in vivo. Both Ly294002 and U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, reduced invasion, which correlated with reduction of the metalloproteinase matrix metalloproteinase 2. Tumor angiogenesis was disrupted through inhibition of vascular endothelial growth factor production from the tumor cells and antiangiogenic effects on endothelial cells. Observations with TPras melanoma cells that express dominant negative Δp85 or kinase-inactive Raf301 supported the specificity of the phenomena observed with the chemical inhibitors. These studies demonstrate that topical treatment targeting Ras effectors is efficacious, without systemic toxicities, and may prove to be useful in treating and preventing the progression of cutaneous melanoma.

Original languageEnglish (US)
Pages (from-to)2552-2560
Number of pages9
JournalCancer Research
Volume64
Issue number7
DOIs
StatePublished - Apr 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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