Targeting matrix metalloproteinases and endothelial cells with a fusion peptide against tumor.
Development of novel therapy for patients with tumor is still a challenge at the present time. We designed a fusion peptide (RK5) with two targets as a novel agent against tumor. The fusion peptide RK5 containing the kringle 5 fragment of human plasminogen and a decapeptide (CTTHWGFTLC) was constructed and expressed in yeast. Matrix metalloproteinase (MMP) activity, proliferation, and migration of endothelial cells were examined in vitro, respectively. Angiogenesis, tumor growth, metastasis, and survival time were evaluated in in vivo models. Administration of RK5 was delivered by both protein and gene approach. The results showed that RK5 inhibited the activity of MMP-9 and exhibited more inhibitory effects on proliferation and migration of endothelial cells than that of kringle 5 fragment and decapeptide individually. RK5 also inhibited angiogenesis, tumor growth, and metastasis and increased survival time of mice bearing tumor. In addition, the effectiveness of RK5 could be achieved by both protein and gene delivery. In conclusion, RK5 has potential to inhibit tumor growth and metastasis and to prolong survival time of animals bearing tumor. Therefore, fusion peptide RK5 with two targets provides a new design for the development of antitumor drugs and has potential for clinical application.
Zou
Yufei
Y
National Key Laboratory of Protein Engineering and Plant Gene Engineering, College of Life Sciences, Peking University, China.
Chen
Yahui
Y
Jiang
Yongqiang
Y
Gao
Jin
J
Gu
Jun
J
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000201:enzymology*; D006801:Humans; D018082:Kringles; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009842:Oligopeptides / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; D010958:Plasminogen; D020782:Matrix Metalloproteinases