Short pigment epithelial-derived factor-derived peptide inhibits angiogenesis and tumor growth

Yelena Mirochnik, Arin Aurora, Frank T. Schulze-Hoepfner, Ahmed Deabes, Victor Shifrin, Richard Beckmann, Charles Polsky, Olga V. Volpert

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60 Scopus citations

Abstract

Purpose: Pigment epithelial-derived factor (PEDF) isa potent angiogenesis inhibitor with multiple other functions, some of which enhance tumor growth. Our previous studies mapped PEDF antiangiogenic and prosurvival activities to distinct epitopes. This study was aimed to determine the minimal fragment of PEDF, which maintains antiangiogenic and antitumor efficacy. Experimental Design: We analyzed antigenicity, hydrophilicity, and charge distribution of the angioinhibitory epitope (the 34-mer) and designed three peptides covering its COOH terminus, P14, P18, and P23. We analyzed their ability to block endothelial cell chemotaxisand induce apoptosis in vitro and their antiangiogenic activity in vivo. The selected peptide was tested for the antitumor activity against mildly aggressive xenografted prostate carcinoma and highly aggressive renal cell carcinoma. To verify that P18 acts in the same manner as PEDF, we used immunohistochemistry to measure PEDF targets, vascular endothelial growth factor receptor 2, and CD95 ligand expression in P18-treated vasculature. Results: P14 and P18 blocked endothelial cell chemotaxis; P18 and P23 induced apoptosis. P18 showed the highest IC 50 and blocked angiogenesis in vivo: P23 wasinactive and P14 was proangiogenic. P18 increased the production of CD95 ligand and reduced the expression of vascular endothelial growth factor receptor 2 by the endothelial cells in vivo. In tumor studies, P18 was more effective in blocking the angiogenesis and growth of the prostate cancer than parental 34-mer; in the renal cell carcinoma, P18 strongly decreased angiogenesis and halted the progression of established tumors. Conclusions: P18 isa novel and potent antiangiogenic biotherapeutic agent that has potential to be developed for the treatment of prostate and renal cancer.

Original languageEnglish (US)
Pages (from-to)1655-1663
Number of pages9
JournalClinical Cancer Research
Volume15
Issue number5
DOIs
StatePublished - Mar 1 2009

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Mirochnik, Y., Aurora, A., Schulze-Hoepfner, F. T., Deabes, A., Shifrin, V., Beckmann, R., Polsky, C., & Volpert, O. V. (2009). Short pigment epithelial-derived factor-derived peptide inhibits angiogenesis and tumor growth. Clinical Cancer Research, 15(5), 1655-1663. https://doi.org/10.1158/1078-0432.CCR-08-2113