Kringle 5 of Plasminogen is a Novel Inhibitor of Endothelial Cell Growth

Cao, Yihai; Chen, Andrew; An, Seong Soo A.; Ji, Richard-Weidong; Davidson, Donald J.; Cao, Yumei; Llinás, Miguel

doi:10.1074/jbc.272.36.22924

Cited by 272 publications

(233 citation statements)

References 34 publications

Supporting

Mentioning

223

Contrasting

Unclassified

Order By: Relevance

“…5 It has been demonstrated that other fragments of plasminogen, such as the first three kringle (K1-3) domains and kringle 5 (K5) exhibit potent inhibitory activities on endothelial cell proliferation. 8,9 Inhibition of angiogenesis by treatment with angiostatin causes significant suppression of tumor growth in both murine and human tumor models. 5,[10][11][12] Gene therapy strategies against cancer by transfer of a DNA sequence encoding the region of plasminogen corresponding to angiostatin have been applied in different tumor models.…”

Section: Introductionmentioning

confidence: 99%

A novel strategy for the generation of angiostatic kringle regions from a precursor derived from plasminogen

et al. 2002

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

A novel strategy for the generation of angiostatic kringle regions from a precursor derived from plasminogen

et al. 2002

View full text Add to dashboard Cite

“…1A) is composed of CTT peptide (an MMP-2/9 inhibitory peptide, CTTHWGFTLC), endostatin mimic (N terminal 25 aa of the native molecule), and kringle 5 fragment of plasminogen (7,12,23). AARP represents antiangiogenic recombinant protein.…”

Section: Characterization and Preparation Of Aarpa And Aarpbmentioning

confidence: 99%

“…Here, we report a novel triple fusion antiangiogenic protein, AARP, consisting of endostatin mimic (NH 2 -terminal 25-amino acid peptide of endostatin), an MMP-2/9-selective inhibitory peptide (CTTHWGFTLC), and kringle 5 fragment of human plasminogen (7,12,23). We reasoned that this triple fusion protein would increase the half-life of endostatin mimic peptide, enhance antiangiogenic activity of RK5 (CTT peptide-kringle 5) or endostatin mimic peptide.…”

Section: Introductionmentioning

confidence: 99%

“…Kringle 5 is a proteolytic fragment of plasminogen, consisting of 80 amino acids (7). On the basis of in vitro assays, kringle 5 has more potent antiangiogenic activity than angiostatin (7,8). Kringle 5 has been shown to inhibit angiogenesis by inducing the cellcycle arrest, autophagy, and apoptosis of proliferating endothelial cells (8,9).…”

Section: Introductionmentioning

confidence: 99%

“…Angiostatin (kringles 1-4), an endogenous angiogenesis inhibitor of 38 kDa internal fragment of plasminogen (contains kringles 1-5), which was originally identified from mice bearing a Lewis lung carcinoma (LLC) because of its ability to inhibit the growth of established metastases (6). Kringle 5 is a proteolytic fragment of plasminogen, consisting of 80 amino acids (7). On the basis of in vitro assays, kringle 5 has more potent antiangiogenic activity than angiostatin (7,8).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Therapeutic Targeting of Angiogenesis with a Recombinant CTT Peptide–Endostatin Mimic–Kringle 5 Protein

Wang

Yang

2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Angiogenesis is required for tumor growth and metastasis, and targeting angiogenesis is a novel anticancer strategy. However, cancer development is a complex multistep process, and single antiangiogenic agents have limited therapeutic efficacy. Here, we report a triple fusion protein, namely CTT peptideendostatin mimic-kringle 5 (AARP), consisting of MMP-2/9-selective inhibitory peptide (CTT peptide) and well-known endogenous antiangiogenic agents (endostatin mimic and kringle 5), which can simultaneously target matrix metalloproteinases (MMP) and endothelial cells, blocking their actions. AARP was bacterially expressed, and biologic activity of purified AARP was assessed. AARP could significantly inhibit the enzymatic activity of MMP-2/9, proliferation, migration, and tube formation of endothelial cells in vitro. The antitumor activity of AARP was shown in a concentration-dependent manner when injected i.p. into immunodeficient mice bearing multidrug-resistant human epidermoid carcinomas (KB), and AARP is superior to clinical grade endostatin in inhibiting KB xenograft growth. In mouse models of Lewis lung carcinoma (LLC) and hepatoma H22, when given as a single dose, AARP is highly effective for reducing tumor growth, angiogenesis, and metastasis, and increasing survival time. AARP possessed significantly greater antiangiogenic activity than endostatin mimic, CTT peptide-kringle 5 (RK5) both in vitro and in vivo. Compared with conventional chemotherapeutic agents (cyclophosphamide and paclitaxel), AARP is also effective. More importantly, AARP is cytocompatible and no tissue toxicity could be observed after large dose administration. Taken together, our findings suggest AARP is a highly effective, safe, and more potent antiangiogenic agent for blocking tumor angiogenesis and metastasis, and warrants further testing for clinical applications.

show abstract

Angiostatin generation by human tumor cell lines: Involvement of plasminogen activators

Westphal¹,

Hullenaar²,

Geurts-Moespot³

et al. 2000

Int. J. Cancer

View full text Add to dashboard Cite

Kringle 5 of Plasminogen is a Novel Inhibitor of Endothelial Cell Growth

Cited by 272 publications

References 34 publications

A novel strategy for the generation of angiostatic kringle regions from a precursor derived from plasminogen

A novel strategy for the generation of angiostatic kringle regions from a precursor derived from plasminogen

Therapeutic Targeting of Angiogenesis with a Recombinant CTT Peptide–Endostatin Mimic–Kringle 5 Protein

Angiostatin generation by human tumor cell lines: Involvement of plasminogen activators

Contact Info

Product

Resources

About