Suppression of tumor growth and angiogenesis by a specific antagonist of the cell-surface expressed nucleolin.
BACKGROUND
Emerging evidences suggest that nucleolin expressed on the cell surface is implicated in growth of tumor cells and angiogenesis. Nucleolin is one of the major proteins of the nucleolus, but it is also expressed on the cell surface where is serves as a binding protein for variety of ligands implicated in cell proliferation, differentiation, adhesion, mitogenesis and angiogenesis.


RESULTS
By using a specific antagonist that binds the C-terminal tail of nucleolin, the HB-19 pseudopeptide, here we show that the growth of tumor cells and angiogenesis are suppressed in various in vitro and in vivo experimental models. HB-19 inhibited colony formation in soft agar of tumor cell lines, impaired migration of endothelial cells and formation of capillary-like structures in collagen gel, and reduced blood vessel branching in the chick embryo chorioallantoic membrane. In athymic nude mice, HB-19 treatment markedly suppressed the progression of established human breast tumor cell xenografts in nude mice, and in some cases eliminated measurable tumors while displaying no toxicity to normal tissue. This potent antitumoral effect is attributed to the direct inhibitory action of HB-19 on both tumor and endothelial cells by blocking and down regulating surface nucleolin, but without any apparent effect on nucleolar nucleolin.


CONCLUSIONS
Our results illustrate the dual inhibitory action of HB-19 on the tumor development and the neovascularization process, thus validating the cell-surface expressed nucleolin as a strategic target for an effective cancer drug. Consequently, the HB-19 pseudopeptide provides a unique candidate to consider for innovative cancer therapy.
CNRS UMR 7149, Université Paris-Est, Créteil, France.
Damien
D
Destouches
Diala
D
El Khoury
Yamina
Y
Hamma-Kourbali
Bernard
B
Krust
Patricia
P
Albanese
Panagiotis
P
Katsoris
Gilles
G
Guichard
Jean Paul
JP
Briand
José
J
Courty
Ara G
AG
Hovanessian
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010455:Peptides / Q000494:pharmacology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors*; D000097796:Nucleolin
D000970:Antineoplastic Agents; D008565:Membrane Proteins; D010455:Peptides; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C121944:HB-19 peptide