Action of fenretinide (4-HPR) on ovarian cancer and endothelial cells.
BACKGROUND
Fenretinide (4-HPR) is a synthetic retinoid that has been reported to inhibit the growth of cancer cell lines in vitro.


METHODS
We examined the effect of 4-HPR on ovarian cancer (OVCAR-5) cell proliferation, viability and invasion using standard techniques. We also examined the action of 4-HPR on the actin cytoskeleton using immunocytochemistry, and on phosphorylation of focal adhesion kinase (FAK) using immunoprecipitation and phosphotyrosine immunoblotting. We then examined the activity of 4-HPR on endothelial cells using the tube formation assay on Matrigel.


RESULTS
4-HPR inhibited OVCAR-5 cell proliferation and viability at concentrations higher than 1 microM, with 70-90% growth inhibition at 10 microM. 4-HPR (1 microM) significantly inhibited OVCAR-5 invasion after 3 days preincubation. In view of the importance of the cytoskeleton in cell motility, we examined the action of 4-HPR on the actin cytoskeleton and on FAK phosphorylation. In OVCAR-5 cells treated with 1 mM fenretinide for 3 days, actin cytoskeleton stress fibers were disrupted and FAK tyrosine phosphorylation was elevated dose-dependently. Endothelial cells treated with 1 microM 4-HPR failed to form tubes, but formed small cellular aggregates.


CONCLUSIONS
Fenretinide has anti-tumor activity by acting on the actin cytoskeleton and by regulating FAK tyrosine phosphorylation. 4-HPR also inhibits endothelial cell tube formation, a major step in angiogenesis.
Golubkov
Vladislav
V
Departments of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine, Los Angeles, California 90033, USA.
Garcia
Agustin
A
Markland
Francis S
FS
D000199:Actins / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
D000199:Actins; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D017313:Fenretinide; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human