Human endostatin-derived synthetic peptides possess potent antiangiogenic properties in vitro and in vivo

Cattaneo, Maria Grazia; Pola, Sandra; Francescato, Pierangelo; Chillemi, Francesco; Vicentini, Lucia M.

doi:10.1016/s0014-4827(02)00057-5

Cited by 52 publications

(38 citation statements)

References 14 publications

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“…Several groups have shown that peptides derived from endostatin have antiangiogenic effects (29,(37)(38)(39)(40)). An NH 2 -terminal peptide composed of amino acids 6 to 49 (lacking the Zn-binding histidines) has inhibited endothelial cell proliferation and migration (37,38).…”

Section: Discussionmentioning

confidence: 99%

A 27-Amino-Acid Synthetic Peptide Corresponding to the NH2-Terminal Zinc-Binding Domain of Endostatin Is Responsible for Its Antitumor Activity

et al. 2005

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The first recombinant endostatin that elicited strong antitumor activity was expressed in Escherichia coli and administered as a suspension. Under these conditions, the protein retained its full antiangiogenic activity. Lack of requirement for a folded structure prompted us to investigate antitumor properties of synthetic peptides corresponding to different regions of endostatin. Here, we show that the entire antitumor, antimigration, and antipermeability activities of endostatin are mimicked by a 27-amino-acid peptide corresponding to the NH 2 -terminal domain of endostatin. This peptide contains three histidines that are responsible for zinc binding. Mutations of the zinc-binding histidines abolished its antitumor and antimigration activities, but not antipermeability properties. (Cancer Res 2005; 65(9): 3656-63)

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Section: Discussionmentioning

confidence: 99%

A 27-Amino-Acid Synthetic Peptide Corresponding to the NH2-Terminal Zinc-Binding Domain of Endostatin Is Responsible for Its Antitumor Activity

et al. 2005

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“…36,37 Thus, the exact NL-binding sites on ES were mapped according to the report of Cattaneo et al 37 The result indicates that none of the ES fragments binds NL ( Figure 1D-F), which suggests that NL may not mediate the bioactivities of any fragments of ES. Moreover, an ES arginine mutant (R158A, R270A), a heparin-binding site-null mutant, 18 does not bind NL either, implying that the heparin-binding site is critical for the interaction between ES and NL ( Figure 1E,F).…”

Section: Nucleolin Is An Endostatin-binding Proteinmentioning

confidence: 97%

Nucleolin is a receptor that mediates antiangiogenic and antitumor activity of endostatin

Shi

Huang

Zhou

et al. 2007

Blood

213

206

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The exact molecular mechanism of how endostatin inhibits angiogenesis and tumor growth remains uncharacterized. Here, we report that endostatin specifically binds to the cell surface nucleolin with high affinity. Blockage of nucleolin by a neutralizing antibody or knockdown of nucleolin by the RNA interference results in loss of antiendothelial activities of endostatin. Importantly, a neutralizing antinucleolin antibody abrogates the antiangiogenic and antitumor activities of endostatin in vivo. Nucleolin and endostatin are colocalized on the cell surface of endothelial cells of angiogenic blood vessels in the tumor environment. Finally, we found that endostatin is internalized and transported into cell nuclei of endothelial cell via nucleolin. In the nucleus, the phosphorylation of nucleolin, which is critical for cell proliferation, can be inhibited by endostatin. Our studies demonstrate that nucleolin is a novel functional receptor for endostatin, and mediates the antiangiogenic and antitumor activities of endostatin. These findings also provide mechanistic insights of how endostatin specifically inhibits proliferating endothelial cell growth and angiogenesis. IntroductionAngiogenesis, sprouting new blood vessels from existing capillaries, is critical for tumor growth. 1,2 Therefore, antiangiogenic molecules offer new promises as novel therapeutic modalities for the treatment of tumors. Endostatin (ES), a 20-kDa C-terminal globular domain of the collagen XVIII, was originally isolated from the supernatant of a cultured murine hemangioendothelioma cell line for its ability to inhibit tumor angiogenesis. 3 In animal models, tumor dormancy could be induced by repeated administration of ES for several cycles without causing drug resistance. 4 Moreover, low toxicity of ES has been reported in both animal studies and human trials. [4][5][6] ES exhibits potent anti-endothelial cell activities including inhibition of cell proliferation, migration, adhesion, and survival, which are all required for angiogenesis in vivo. 3,[7][8][9][10][11] The exact molecular mechanism of ES still remains an enigma, although a number of ES-binding proteins such as integrins, tropomyosin, glypicans, laminin, and MMP2 have been reported as ES receptors. 9,[12][13][14][15] However, whether these ES receptors are involved in the antitumor function of ES remains elusive. Recently, using DNA gene microarray and proteomic analysis, Huber and colleagues have identified a number of potential intracellular targets of ES (Abdollahi et al 16 ). Nevertheless, several antiangiogenic-related properties of ES remain uncharacterized, and they have raised several critical unexplored issues at the molecular level. These include (1) Why does ES specifically target angiogenic blood vessels but not quiescent blood vessels 17 ? (2) Why does ES specifically inhibit tumor growth and produce little if any toxicity in animal studies and clinical trials 4-6 ? (3) Why are heparin-binding sites required for the angiostatic activities of ES 18 ? To unravel these p...

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“…The migration assays were performed in a 24-well modified Boyden chamber as described earlier [9]. In brief, 8 μm cell culture inserts (BD Biosciences) coated with 0.2 % gelatin (Sigma) were placed over the bottom chamber containing 20 ng/ml VEGF as the chemoattractant.…”

Section: Migration Assaymentioning

confidence: 99%

Pharmacological inhibition of poly(ADP-ribose) polymerase inhibits angiogenesis

Rajesh

Mukhopadhyay

Bátkai

et al. 2006

Biochemical and Biophysical Research Communications

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Poly(ADP-ribose)polymerase (PARP) is a nuclear enzyme which plays an important role in regulating cell death and cellular responses to DNA repair. Pharmacological inhibitors of PARP are being considered as treatment for cancer both in monotherapy as well as in combination with chemotherapeutic agents and radiation, and were also reported to be protective against untoward effects exerted by certain anticancer drugs.Here we show that pharmacological inhibition of PARP with 3-aminobenzamide or PJ-34 dosedependently reduces VEGF-induced proliferation, migration and tube formation of human umbilical vein endothelial cells in vitro.These results suggest that treatment with PARP inhibitors may exert additional benefits in various cancers and retinopathies by decreasing angiogenesis.

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Human endostatin-derived synthetic peptides possess potent antiangiogenic properties in vitro and in vivo

Cited by 52 publications

References 14 publications

A 27-Amino-Acid Synthetic Peptide Corresponding to the NH2-Terminal Zinc-Binding Domain of Endostatin Is Responsible for Its Antitumor Activity

A 27-Amino-Acid Synthetic Peptide Corresponding to the NH2-Terminal Zinc-Binding Domain of Endostatin Is Responsible for Its Antitumor Activity

Nucleolin is a receptor that mediates antiangiogenic and antitumor activity of endostatin

Pharmacological inhibition of poly(ADP-ribose) polymerase inhibits angiogenesis

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