title: Therapeutic targeting of angiogenesis with a recombinant CTT peptide-endostatin mimic-kringle 5 protein.
abstract: 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 peptide-endostatin 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.
authors.affiliation: National Key Laboratory of Protein and Plant Gene Research, LSC, Peking University, Beijing, China.
authors.forename: Houbin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Hematology, Affiliated Hospital of Guangdong Medical College, Guangzhou, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: National Key Laboratory of Protein and Plant Gene Research, LSC, Peking University, Beijing, China. Department of Hematology, Affiliated Hospital of Guangdong Medical College, Guangzhou, China. gj@pku.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000188:drug therapy; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D043169:Endostatins / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D018082:Kringles; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; C415426:CTTHWGFTLC peptide; D043169:Endostatins; D010456:Peptides, Cyclic; D011993:Recombinant Fusion Proteins