L-5F, an apolipoprotein A-I mimetic, inhibits tumor angiogenesis by suppressing VEGF/basic FGF signaling pathways.

Academic Article

Abstract

  • We recently reported that apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor growth and improve survival in a mouse model of ovarian cancer. The current study was designed to examine whether inhibition of angiogenesis is one of the mechanisms for the observed anti-tumorigenic effects. The apoA-I mimetic peptide L-5F had no affect on proliferation and cell viability of human umbilical vascular endothelial cells (HUVECs) in the basal state; however, treatment with L-5F at 1, 3, and 10 μg ml(-1), dose-dependently inhibited both vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF)-induced proliferation, cell viability, migration, invasion and tube formation in HUVECs. L-5F inhibited VEGF- and bFGF-induced activation of their corresponding receptors, VEGFR2 and FGFR1, as well as downstream signaling pathways, including Akt and ERK1/2. MicroCT scanning and immunohistochemistry staining demonstrated that daily injection of L-5F (10 mg kg(-1)) decreased both the quantity and size of tumor vessels in mice. L-5F treated mice showed significantly reduced levels of VEGF in both tumor tissue and the circulation, which is consistent with in vitro data showing that L-5F inhibited production and secretion of VEGF from mouse and human ovarian cell lines in the absence and presence of exogenously added lysophosphatidic acid, a potent tumor promoter. In conclusion, our data that L-5F inhibits angiogenesis suggests that apoA-I mimetic peptides may serve as novel anti-angiogenesis agents for the treatment of angiogenesis-associated diseases, including cancer.
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    Keywords

  • Amino Acid Sequence, Angiogenesis Inhibitors, Animals, Apolipoprotein A-I, Blood Vessels, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Survival, Cells, Cultured, Endothelial Cells, Extracellular Signal-Regulated MAP Kinases, Female, Fibroblast Growth Factor 2, Gene Expression, Humans, Lysophospholipids, Mice, Mice, Inbred C57BL, Models, Biological, Molecular Mimicry, Molecular Sequence Data, Neovascularization, Pathologic, Neovascularization, Physiologic, Ovarian Neoplasms, Peptide Fragments, Peptides, Phosphorylation, Proto-Oncogene Proteins c-akt, Receptor, Fibroblast Growth Factor, Type 1, Signal Transduction, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2
  • Digital Object Identifier (doi)

    Author List

  • Gao F; Vasquez SX; Su F; Roberts S; Shah N; Grijalva V; Imaizumi S; Chattopadhyay A; Ganapathy E; Meriwether D
  • Start Page

  • 479
  • End Page

  • 489
  • Volume

  • 3
  • Issue

  • 4