Targeting Matrix Metalloproteinases and Endothelial Cells with a Fusion Peptide against Tumor

Abstract

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. [Cancer Res 2007;67(15):7295-300]

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

“…Importantly, synthetic and recombinant CTT peptides showed nearly identical inhibitory activities against MMP-2 and MMP-9 (25,(30)(31)(32)(33). In our previous study, we found recombinant CTT peptide, when fused with kringle 5, could inhibit MMP-9 caseinolytic activity in a concentration-dependent manner (25).…”

“…Construction, expression, and characterization of RK5, AARP RK5 was expressed and purified according to Zou and colleagues (25). cDNA encoding triple fusion protein AARPa and isoform AARPb were amplified with overlap extension PCR.…”

“…AARP represents antiangiogenic recombinant protein. RK5 is a double fusion protein we previously developed, which contains CTT peptide and kringle 5 (25). There could be two variants of triple fusion protein when 25 aa fused with RK5 as illustrated in Fig.…”

Recent Advances in the Development of MMPIs and APNIs Based on the Pyrrolidine Platforms

“…44 WenhuaXi Road, Ji'nan, 250012, Shandong Province, P.R. China; Tel: 86-531-88382011; Fax: 86-531-88382264; E-mail: tjulx2004@sdu.edu.cn components, which are believed to contribute to a wide array of pathological conditions related to tumor metastasis, angiogenesis, cardiovascular disease, osteoarthritis, rheumatoid arthritis, chronic periodontitis, pulmonary emphysema, skin ulceration, atherosclerosis, central nervous system disease, type I diabetes, myocarditis and dilated cardiomyopathy, coronary artery disease, multiple sclerosis, congestive heart failure, and so forth [5][6][7][8][9][10][11]. Accordingly, effective controlling MMP activity(s) using natural or synthetic smallmolecule inhibitors (MMPIs) represents an attractive and potential area of drug development to intervene in the MMPrelated disorders [12,13].…”

Sulfonyl phosphonic 1,4-dithia-7-azaspiro[4,4]nonane derivatives as matrix metalloproteinase inhibitors: Synthesis, a docking study, and biological evaluation

“…MMPs are minimally expressed and strictly regulated at multiple levels to ensure proper functioning in physiological processes, whereas their overexpression and excessive activity have been implicated in a variety of pathological disorders ranging from cardiovascular disease to cancer (4)(5)(6)(7). Of all of the identified MMP subtypes, MMP-2, also known as gelatinase A due to its close correlation with tumor progression (8)(9)(10), has been considered an attractive target for structurebased drug design, and research on MMP-2 inhibitors is a very promising strategy for cancer therapy and development of anticancer drugs (11).…”