Short pigment epithelial-derived factor-derived peptide inhibits angiogenesis and tumor growth.
OBJECTIVE
Pigment epithelial-derived factor (PEDF) is a 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.


METHODS
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 chemotaxis and 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 IC50 and blocked angiogenesis in vivo: P23 was inactive 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 is a novel and potent antiangiogenic biotherapeutic agent that has potential to be developed for the treatment of prostate and renal cancer.
Mirochnik
Yelena
Y
Urology Department, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Aurora
Arin
A
Schulze-Hoepfner
Frank T
FT
Deabes
Ahmed
A
Shifrin
Victor
V
Beckmann
Richard
R
Polsky
Charles
C
Volpert
Olga V
OV
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002633:Chemotaxis; D016510:Corneal Neovascularization; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005136:Eye Proteins / Q000737:chemistry*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009414:Nerve Growth Factors / Q000737:chemistry*; D010446:Peptide Fragments / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D015843:Serpins / Q000737:chemistry*; D014471:Umbilical Veins / Q000166:cytology; D000099174:Pigment Epithelium-Derived Factor
D020533:Angiogenesis Inhibitors; D005136:Eye Proteins; D009414:Nerve Growth Factors; D010446:Peptide Fragments; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor