The human prothrombin kringle-2 protein inhibits angiogenesis and LLC (Lewis lung carcinoma) growth and metastasis in mice. Additionally, the NSA9 peptide (NSAVQLVEN) derived from human prothrombin kringle-2 has been reported to inhibit the proliferation of BCE (bovine capillary endothelial) cells and CAM (chorioallantoic membrane) angiogenesis. In the present study, we examined the structure–activity relationships of the NSA9 peptide in inhibiting the proliferation of endothelial cells lines e.g. BCE and HUVE (human umbilical vein endothelial). N- or C-terminal truncated derivatives and reverse sequence analogues of NSA9 were prepared and their anti-proliferative activities were assessed using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay. This cell proliferation assay demonstrated that both the N-terminal region and sequence orientation of NSA9 are important for inhibiting the proliferation of endothelial cells. In particular 2 C-terminal truncation derivatives of NSA9 [NSA7 (NSAVQLV) and NSA8 (NSAVQLVE)] inhibited cellular proliferation to a greater extent than did NSA9. The heptapeptide NSA7, was found to be more potent than NSA9 in inhibiting CAM angiogenesis, and tubular formation and migration of HUVE cells. In addition NSA9, NSA8 and NSA7 peptides exhibited considerable inhibitory effects on the proliferation of tumour cells such as B16F10 (murine melanoma), LLC and L929 (murine fibroblast). Also, cellular internalization studies demonstrated that NSA7 was internalized into both endothelial and tumour cells more easily than was NSA9. In conclusion, these results suggest that NSA7, residing within the full sequence of NSA9, contains the required sequence for anti-proliferative activity and cellular internalization.
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Research Article|
March 15 2006
Structure–activity relationships of the human prothrombin kringle-2 peptide derivative NSA9: anti-proliferative activity and cellular internalization
Hyun Sook Hwang;
Hyun Sook Hwang
1Department of Biochemistry, College of Science, Yonsei University, Seoul 120-749, Korea
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Dong Won Kim;
Dong Won Kim
1Department of Biochemistry, College of Science, Yonsei University, Seoul 120-749, Korea
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Soung Soo Kim
Soung Soo Kim
1
1Department of Biochemistry, College of Science, Yonsei University, Seoul 120-749, Korea
1To whom correspondence should be addressed (email kimss518@yonsei.ac.kr).
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Publisher: Portland Press Ltd
Received:
August 09 2005
Revision Received:
November 14 2005
Accepted:
January 03 2006
Accepted Manuscript online:
January 03 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 395 (1): 165–172.
Article history
Received:
August 09 2005
Revision Received:
November 14 2005
Accepted:
January 03 2006
Accepted Manuscript online:
January 03 2006
Citation
Hyun Sook Hwang, Dong Won Kim, Soung Soo Kim; Structure–activity relationships of the human prothrombin kringle-2 peptide derivative NSA9: anti-proliferative activity and cellular internalization. Biochem J 1 April 2006; 395 (1): 165–172. doi: https://doi.org/10.1042/BJ20051300
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